Chemical Compounds

ABSTRACT

The invention relates to methods for the treatment of medical conditions comprising administering an effective amount of a compound of formula (I): 
     
       
         
         
             
             
         
       
     
     wherein all variables are as defined herein.

CROSS REFERENCE TO RELATED APPLICATIONS

This application is a continuation of U.S. patent application Ser. No.11/334,267, filed 18 Jan. 2008, (issue fee paid); which is acontinuation of U.S. patent application Ser. No. 10/637,825, filed 8Aug. 2003, now U.S. Pat. No. 7,071,196, which is a continuation of Ser.No. 10/190,170, filed 3 Jul. 2002, now U.S. Reissue Pat. No. RE39921;which is a reissue of U.S. Pat. No. 6,642,240; which is a continuationof U.S. patent application Ser. No. 10/089,964, filed 8 May 2002, nowU.S. Pat. No. 6,951,861, which was filed pursuant to 35 U.S.C. §371 as aUnited States National Phase Application of International ApplicationNo. PCT/EP00/09722, filed 5 Oct. 2000, which claims priority to GreatBritain Priority Patent Application Serial No. 9923748.9, filed 7 Oct.1999.

The present invention relates to piperazine derivatives, to processesfor their preparation, to pharmaceutical compositions containing themand to their medical use.

In particular the invention relates to novel compounds which are potentand specific antagonists of tachykinins, including substance P and otherneurokinins.

The present invention provides compounds of formula (I)

whereinR represents a halogen atom or a C₁₋₄ alkyl group;R₁ represents hydrogen or a C₁₋₄ alkyl group;R₂ represents hydrogen or a C₁₋₄ alkyl group;R₃ represents a trifluoromethyl, a C₁₋₄ alkyl, a C₁₋₄ alkoxy, atrifluoromethoxy or a halogen group;R₄ represents hydrogen, a (CH₂)qR₇ or a (CH₂)rCO(CH₂)pR₇ group;R₅ represents hydrogen, a C₁₋₄ alkyl or a COR₆ group;R₆ represents hydrogen, hydroxy, amino, methylamino, dimethylamino, a 5membered heteroaryl group containing 1 to 3 heteroatoms selectedindependently from oxygen, sulphur and nitrogen or a 6 memberedheteroaryl group containing 1 to 3 nitrogen atoms;R₇ represents hydrogen, hydroxy, or NR₈R₉ wherein R₈ and R₉ representindependently hydrogen or C₁₋₄ alkyl optionally substituted by hydroxyor by amino;R₁₀ represents hydrogen;m is zero or an integer from 1 to 3; n is zero or an integer from 1 to3; bothp and r are independently zero or an integer from 1 to 4; q is aninteger from 1 to 4;and pharmaceutically acceptable salts and solvates thereof.

A further embodiment of the invention provides compounds of formula (I)and pharmaceutically acceptable salts and solvates thereof, wherein

R represents a halogen atom or a C₁₋₄ alkyl group;R₁ represents hydrogen or a C₁₋₄ alkyl group;R₂ represents hydrogen, a C₁₋₄ alkyl, C₂₋₆ alkenyl- or a C₃₋₇ cycloalkylgroup; or R₁ and R₂ together with nitrogen and carbon atom to which theyare attached respectively represent a 5 to 6 membered heterocyclicgroup;R₃ represents a trifluoromethyl, a C₁₋₄ alkyl, a C₁₋₄ alkoxy, atrifluoromethoxy or a halogen group;R₄ represents hydrogen, a (CH₂)qR₇ or a (CH₂)rCO(CH₂)pR₇ group;R₅ represents hydrogen, a C₁₋₄ alkyl or a COR₆ group;R₆ represents hydrogen, hydroxy, amino, methylamino, dimethylamino a 5membered heteroaryl group containing 1 to 3 heteroatoms selected fromoxygen, sulphur and nitrogen or a 6 membered heteroaryl group containing1 to 3 nitrogen atoms;R₇ represents hydrogen, hydroxy or NR₈R₉ wherein R₈ and R₉ representindependently hydrogen or C₁₋₄ alkyl optionally substituted by hydroxyor by amino;R₁₀ represents hydrogen, a C₁₋₄ alkyl group orR₁₀ together with R₂ represents a C₃₋₇ cycloalkyl group;m is zero or an integer from 1 to 3; n is zero or an integer from 1 to3; both p and r are independently zero or an integer from 1 to 4; q isan integer from 1 to 4; provided that, when R₁ and R₂ together withnitrogen and carbon atom to which they are attached respectivelyrepresent a 5 to 6 membered heterocyclic group, i) m is 1 or 2; ii) whenm is 1, R is not fluorine and iii) when m is 2, the two substituents Rare not both fluorine.

Suitable pharmaceutically acceptable salts of the compounds of generalformula (I) include acid addition salts formed with pharmaceuticallyacceptable organic or inorganic acids, for example hydrochlorides,hydrobromides, sulphates, alkyl- or arylsulphonates (e.g.methanesulphonates or p-toluenesulphonates), phosphates, acetates,citrates, succinates, tartrates, fumarates and maleates.

The solvates may, for example, be hydrates.

References hereinafter to a compound according to the invention includeboth compounds of formula (I) and their pharmaceutically acceptable acidaddition salts together with pharmaceutically acceptable solvates.

It will be appreciated by those skilled in the art that the compounds offormula (I) contain at least one chiral centre (namely the carbon atomshow as * in formula (I)).

Further asymmetric carbon atoms are possible in the compounds of formula(I).

Thus, for example, when R₂ is a C₁₋₄ alkyl, a C₂₋₆ alkenyl or a C₃₋₇cycloalkyl group, and R₅ and R₁₀ are hydrogens, the compounds of formula(I) possess two asymmetric carbon atoms and these may be represented bythe formulae (1a, 1b, 1c and 1d)

The wedge shaped bond indicates that the bond is above the plane of thepaper. The broken bond indicates that the bond is below the plane of thepaper.

The configuration shown for the chiral carbon atom indicated as * informulae 1b and 1d is hereinafter referred to as the β configuration andin formulae 1a and 1c as α configuration.

In general, in the specific compounds named below, the β configurationat the chiral carbon atom indicated as * corresponds to the S isomer andthe α configuration corresponds to the R isomer.

The configuration of the two chiral carbon atoms shown in formulae 1aand 1b is hereinafter referred to as anti configuration and in formulae1c and 1d as the syn configuration.

Furthermore, when R₂ is a C₁₋₄ alkyl, a C₂₋₆ alkenyl or a C₃₋₇cycloalkylgroup or R₁₀ is a C₁₋₄ alkyl group and R₅ is a C₁₋₄ alkyl or a COR₆group, the compounds of the invention possess three asymmetric carbonatoms.

The assignment of the R and S configuration of the asymmetric carbonatoms of the compounds of the invention has been made according to therules of Chan, Ingold and Prelong 1956, 12, 81.

It is to be understood that all enantiomers and diastereisomers andmixtures thereof are encompassed within the scope of the presentinvention.

The term alkyl as used herein as a group or a part of the group refersto a straight or branched alkyl group containing from 1 to 4 carbonatoms; examples of such groups include methyl, ethyl, propyl, isopropyl,n-butyl, isobutyl, or tert butyl.

The term halogen refers to a fluorine, chlorine, bromine or iodine atom.

The term C₂₋₆ alkenyl defines straight or branched chain hydrocarbonradicals containing one double bond and having from 2-6 carbon atomssuch as, for example, ethenyl, 2-propenyl, 3-butenyl, 2-butenyl,2-pentenyl, 3-pentenyl, 3-methyl-2-butenyl or 3-hexenyl.

The term C₃₋₇ cycloalkyl group means a non aromatic monocyclichydrocarbon ring of 3 to 7 carbon atom such as, for example,cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl.

The term C₁₋₄ alkoxy group may be a straight or a branched chain alkoxygroup, for example methoxy, ethoxy, propoxy, prop-2-oxy, butoxy,but-2-oxy or methylprop-2-oxy.

When R₁ and R₂ together with nitrogen and carbon atom to which they areattached respectively represent a 5 to 6 membered heterocyclic groupthis group is saturated or contains a single double bond. This may be a3,6-dihydro-2H-pyridin-1-yl, a piperidin-1-yl or a pyrrolidin 1-ylgroup.

When R₆ is a 5 or 6 membered heteroaryl group according to the inventionthey include furanyl, thiophenyl, imidazolyl, thiazolyl, oxazolyl,pyridyl or pyrimidinyl.

The group R₅ may be in position 3, 5 or 6 of the piperazine ring ofcompounds of formula (I)

When R represents halogen this is suitably chlorine or more preferablyfluorine or when R is C₁₋₄ alkyl this is suitably methyl or ethylwherein m is 0 or an integer from 1 to 2.

Suitable values for R₁ include hydrogen, a methyl, an ethyl or a propylgroup.

Suitable values for R₂ include hydrogen, a methyl, an ethyl a propyl, anisopropyl, a 2-propenyl or a cyclopropyl group.

Suitable values for R₃ include a methyl, an ethyl or a trifluoromethylgroup.

When R₄ is (CH₂)_(q)R₇ or (CH₂)_(r)CO(CH₂)_(p)R₇, R₇ is suitablyhydrogen, hydroxy, NR₉R₈ e.g. NH₂, NH(C₁₋₄ alkyl) e.g. NH methyl orN(C₁₋₄ alkyl)₂ e.g. N(methyl)₂, NH(C₁₋₄ alkyl)NH₂ e.g. NH(ethyl)NH₂,NH(C₁₋₄alkyl) wherein q is 1 or 2 and both p and r are independentlyzero or an integer from 1 to 2.

Suitable values for R₅ include hydrogen or a C₁₋₄ alkyl (e.g. methyl)group.

R is preferably a halogen atom (e.g. fluorine or chlorine) and/or a C₁₋₄alkyl (e.g. methyl) group and m is preferably an integer from 1 to 2.Suitable values for R₁₀ include hydrogen, a C₁₋₄ alkyl (e.g. methyl)group or together with R₂ represents a C₃₋₇ cycloalkyl (i.e.cyclopropyl) group.

R₁ is preferably a hydrogen atom or a methyl group.

R₂ is preferably a hydrogen atom, a methyl, isopropyl, 2-propenyl, or acyclopropyl group or together with R₁ is a 3,6-dihydro-2H-pyridin-1yl, apiperidin-1-yl or a pyrrolidin 1-yl group.

R₃ is preferably a trifluoromethyl group.

R₄ is preferably a hydrogen atom, an amino C₁₋₄ alkyl(e.g. aminoethyl),an aminoacetyl or an amino(C₁₋₄alkylaminocarbonyl) group.

R₅ is preferably a hydrogen atom, a methyl or ethyl group.

R₁₀ is preferably a hydrogen atom, a methyl group or together with R₂ iscyclopropyl.

A preferred group of compounds of formula (I) are those in which thecarbon atom shown as * is in the β configuration.

A preferred class of compounds of formula (I) are those wherein R isselected independently from a halogen or a methyl group, wherein m is 1or 2. More preferably m is 2. Within this class those wherein R is atthe 2 and 4 position are particularly preferred.

Compounds of formula (I) wherein R₃ is a trifluoromethyl group and n is2 represent a preferred class of compounds and within this class R₃ ispreferably at the 3 and 5 position.

A further preferred class of compounds of formula (I) are those whereinR₄ is hydrogen, a (CH₂)rCO(CH₂)pR₇ or (CH₂)qR₇ group, wherein R₇represents an amine. Within this class, those wherein both p and r areindependently zero or 1 or q is 1 or 2 are particularly preferred.

A particularly preferred group of compounds of formula (I) is thatwherein R is selected independently from halogen or methyl, R₃ istrifluoromethyl both at the 3 and 5 position, R₁ is hydrogen or methyl,R₂ is hydrogen, methyl, 2-propenyl, or cyclopropyl group or togetherwith R₁ is a 3,6-dihydro-2H-pyridin-1yl, a piperidin-1-yl or apyrrolidin 1-yl group, R₁₀ represents hydrogen, a methyl or R₁₀ togetherwith R₂ is a cyclopropyl group, R₄ is hydrogen, an aminoacetyl or aminoethyl group and R₅ is hydrogen or a methyl group.

A particularly preferred group of compounds of formula (I) is thatwherein R is selected independently from halogen or methyl, R₃ istrifluoromethyl both at the 3 and 5 position, R₁ is hydrogen or methyl,R₂ is hydrogen, methyl, 2-propenyl or cyclopropyl group or together withR₁ is a 3,6-dihydro-2H-pyridin-1yl, a piperidin-1-yl or a pyrrolidin1-yl group, R₁₀ represents hydrogen, a methyl or R₁₀ together with R₂ isa cyclopropyl group, R₄ is hydrogen, and R₅ is hydrogen.

A further particularly preferred group of compounds of formula (I) isthat wherein R is selected independently from halogen or methyl and m is2, R₃ is trifluoromethyl both at the 3 and 5 position, R₁ and R₂ areindependently hydrogen or methyl, R₄ is hydrogen and R₅ is hydrogen.

Preferred compounds according to the invention are:

-   2-(4-fluoro-2-methyl-phenyl)-piperazine-1-carboxylic acid    (3,5-bis-trifluoromethyl-benzyl)-methyl-amide;-   2-(2-isopropyl-phenyl)-piperazine-1-carboxylic acid    (3,5-bis-trifluoromethyl-benzyl)-methyl-amide;-   2-(4-fluoro-3-methyl-phenyl)-piperazine-1-carboxylic acid    (3,5-bis-trifluoromethyl-benzyl)-methyl-amide;-   2-(2,4-difluoro-phenyl)-piperazine-1-carboxylic acid    (3,5-bis-trifluoromethyl-benzyl)-methyl-amide;-   2-(4-fluoro-2-methyl-phenyl)-piperazine-1-carboxylic acid    [1-(3,5-bis-trifluoromethyl-phenyl)ethyl]-methyl-amide;-   2-(4-fluoro-phenyl)-piperazine-1-carboxylic acid    (3,4-bis-trifluoromethyl-benzyl)-methyl-amide;-   2-Phenyl-piperazine-1-carboxylic acid    (3,5-bis-trifluoromethyl-benzyl)-methyl-amide;-   2-(2,4-dichloro-phenyl)-piperazine-1-carboxylic acid    (3,5-bistrifluoro methyl-benzyl)-methyl-amide;-   2-(3,4-dichloro-phenyl)-piperazine-1-carboxylic acid    (3,5-bistrifluoro methyl-benzyl)-methyl-amide;-   2-(4-fluoro-2-methyl-phenyl)-3-methyl-piperazine-1-carboxylic acid    (3,5-bis-trifluoromethyl-benzyl)-methyl-amide;-   2-(2-methyl-4-fluoro-phenyl)-6-Methyl-piperazine-1-carboxylic acid    (3,5-bis-trifluoromethyl-benzyl)-methyl-amide;-   2-(4-fluoro-2-methyl-phenyl)-piperazine-1-carboxylic acid    [1-(3,5-bis-trifluoromethyl-phenyl)ethyl]-methyl-amide;-   4-(2-Amino-acetyl)-2-(S)-(4-fluoro-2-methyl-phenyl)-piperazine-1-carboxylic    acid (3,5-bis-trifluoromethyl-benzyl)-methyl-amide;-   2-(S)-(4-Fluoro-2-methyl-phenyl)-4-(piperidine-4-carbonyl)-piperazine-1-carboxylic    acid (3,5-bis-trifluoromethyl-benzyl)-methyl-amide;-   4-(2-Amino-ethyl)-2-(S)-(4-fluoro-2-methyl-phenyl)-piperazine-1-carboxylic    acid (3,5-bis-trifluoromethyl-benzyl)-methyl-amide;-   2-(S)-(4-Fluoro-2-methyl-phenyl)-piperazine-1-carboxylic acid    [1-(3,5-bis-trifluoromethyl-phenyl)-cyclopropyl]-methyl-amide;-   [2-(3,5-Bis-trifluoromethyl-phenyl)-pyrrolidin-1-yl]-[2-(S)-(4-fluoro-2-methyl-phenyl)-piperazin-1-yl]-methanone;-   [2-(3,5-Bis-trifluoromethyl-phenyl)-3,6-dihydro-2H-pyridyn-1-yl]-[2-(S)-(4-fluoro-2-methyl-phenyl)-piperazin-1-yl]-methanone;-   [2-(3,5-Bis-trifluoromethyl-phenyl)-piperidin-1-yl]-[2-(S)-(4-fluoro-2-methyl-phenyl)-piperazin-1-yl]-methanone;-   2-(4-Fluoro-2-methyl-phenyl)-piperazine-1-carboxylic acid    [1-(3,5-bis-trifluoromethyl-phenyl)-but-3-enyl]-methyl-amide;-   2-(4-Fluoro-2-methyl-phenyl)-piperazine-1-carboxylic acid    [1-(3,5-bis-trifluoromethyl-phenyl)-2-methyl-propyl]-methyl-amide;-   2-(4-Fluoro-2-methyl-phenyl)-piperazine-1-carboxylic acid    [(3,5-bis-trifluoromethyl-phenyl)-cyclopropyl-methyl]-methyl-amide;    and enantiomers, pharmaceutically acceptable salts (e.g.    hydrochloride, methansulphonate, acetate) and solvates thereof.

Particularly preferred compounds according to the invention are:

-   2-(S)-(4-Fluoro-2-methyl-phenyl)-4-(piperidine-4-carbonyl)-piperazine-1carboxylic    acid (3,5-bis-trifluoromethyl-benzyl)-methyl-amide hydrochloride;-   [2-(3,5-Bis-trifluoromethyl-phenyl)-3,6-dihydro-2H-pyridyn-1-yl]-[2-(S)-(4-fluoro-2-methyl-phenyl)-piperazin-1-yl]-methanone    hydrochloride (enantiomer A);-   4-(2-Amino-acetyl)-2-(S)-(4-fluoro-2-methyl-phenyl)-piperazine-1-carboxylic    acid (3,5-bis-trifluoromethyl-benzyl)-methyl-amide hydrochloride;-   2-(S)-(4-Fluoro-2-methyl-phenyl)-piperazine-1-carboxylic acid    [1-(R)-(3,5-bis-trifluoromethyl-phenyl)-ethyl]-methyl-amide    methansulphonate;-   2-(S)-(4-Fluoro-2-methyl-phenyl)-piperazine-1-carboxylic acid    [1-(R)-(3,5-bis-trifluoromethyl-phenyl)-ethyl]-methyl-amide acetate;    and solvates thereof;

The compounds of the invention are antagonists of tachykinins, includingsubstance P and other neurokinins, both in vitro and in vivo and arethus of use in the treatment of conditions mediated by tachykinins,including substance P and other neurokinins.

NK₁-receptor binding affinity has been determined in vitro by thecompounds' ability to displace [3H]-substance P(SP) from recombinanthuman NK₁ receptors expressed in Chinese Hamster Ovary (CHO) cellmembranes.

CHO cell membranes were prepared by using a modification of the methoddescribed by Dam T and Quirion R (Peptides, 7:855-864, 1986). Thusligand binding was performed in 0.4 ml of 50 mM HEPES, pH 7.4,containing 3 mM MnCl₂, 0.02% BSA, 0.5 nM [³H]Substance P (30÷56 Ci/mmol,Amersham), a final membrane concentration of 25 μg of protein/ml, andthe test compounds. The incubation proceeded at room temperature for 40min. Non-specific binding was determined using excess of Substance P (1μM) and represents about 6% of the total binding.

Compounds of the invention were further characterised in a functionalassay for the determination of their inhibitory effect. Human-NK₁-CHOcells were stimulated with Substance P and the receptor activation wasevaluated by measuring the accumulation ofcytidinediphosphodiacylglycerol (CDP-DAG), which is the liponucleotideprecursor of phosphatidylinositol diphosphate. CDP-DAG accumulates inthe presence of Li⁺ as a consequence of the receptor mediated activationof phospholipase C (PLC) (Godfrey, Biochem. J., 258:621-624, 1989). Themethod is described in detail by Ferraguti et al. (Mol. Cell. Neurosci.,5:269-276, 1994).

The action of the compounds of the invention at the NK₁ receptor may bedetermined by using conventional tests. Thus the ability to bind at theNK₁ receptor was determined using the gerbil foot tapping model asdescribed by Rupniak & Williams, Eur. J. of Pharmacol., 1994.

Compounds of the invention have also been found to exhibit anxiolyticactivity in conventional tests. For example in marmoset human threattest (Costall et al., 1988).

Compounds of the invention may be useful in the treatment of CNSdisorders in particular in the treatment or prevention of majordepressive disorders including bipolar depression, unipolar depression,single or recurrent major depressive episodes with or without psychoticfeatures, catatonic features, melancholic features, atypical features orpostpartum onset, the treatment of anxiety and the treatment of panicdisorders. Other mood disorders encompassed within the term majordepressive disorders include dysthymic disorder with early or late onsetand with or without atypical features, neurotic depression, posttraumatic stress disorders and social phobia; dementia of theAlzheimer's type, with early or late onset, with depressed mood;vascular dementia with depressed mood; mood disorders induced byalcohol, amphetamines, cocaine, hallucinogens, inhalants, opioids,phencyclidine, sedatives, hypnotics, anxiolytics and other substances;schizoaffective disorder of the depressed type; and adjustment disorderwith depressed mood. Major depressive disorders may also result from ageneral medical condition including, but not limited to, myocardialinfarction, diabetes, miscarriage or abortion, etc.

Compounds of the invention are useful as analgesics. In particular theyare useful in the treatment of traumatic pain such as postoperativepain; traumatic avulsion pain such as brachial plexus; chronic pain suchas arthritic pain such as occurring in osteo-, rheumatoid or psoriaticarthritis; neuropathic pain such as post-herpetic neuralgia, trigeminalneuralgia, segmental or intercostal neuralgia, fibromyalgia, causalgia,peripheral neuropathy, diabetic neuropathy, chemotherapy-inducedneuropathy, AIDS related neuropathy, occipital neuralgia, geniculateneuralgia, glossopharyngeal neuralgia, reflex sympathetic dystrophy,phantom limb pain; various forms of headache such as migraine, acute orchronic tension headache, temporomandibular pain, maxillary sinus pain,cluster headache; odontalgia; cancer pain; pain of visceral origin;gastrointestinal pain; nerve entrapment pain; sport's injury pain;dysmennorrhoea; menstrual pain; meningitis; arachnoiditis;musculoskeletal pain; low back pain e.g. spinal stenosis; prolapseddisc; sciatica; angina; ankylosing spondyolitis; gout; burns; scar pain;itch; and thalamic pain such as post stroke thalamic pain.

Compounds of the invention are also useful in the treatment of sleepdisorders including dysomnia, insomnia, sleep apnea, narcolepsy, andcircadian ritmic disorders.

Compounds of the invention are also useful in the treatment orprevention of the cognitive disorders. Cognitive disorders includedementia, amnestic disorders and cognitive disorders not otherwisespecified.

Furthermore compounds of the invention are also useful as memory and/orcognition enhancers in healthy humans with no cognitive and/or memorydeficit.

Compounds of the invention are also useful in the treatment of toleranceto and dependence on a number of substances. For example, they areuseful in the treatment of dependence on nicotine, alcohol, caffeine,phencyclidine (phencyclidine like compounds), or in the treatment oftolerance to and dependence on opiates (e.g. cannabis, heroin, morphine)or benzodiazepines; in the treatment of cocaine, sedative ipnotic,amphetamine or amphetamine-related drugs (e.g. dextroamphetamine,methylamphetamine) addiction or a combination thereof.

Compounds of the invention are also useful as anti-inflammatory agents.In particular they are useful in the treatment of inflammation inasthma, influenza, chronic bronchitis and rheumatoid arthritis; in thetreatment of inflammatory diseases of the gastrointestinal tract such asCrohn's disease, ulcerative colitis, inflammatory bowel disease andnon-steroidal anti-inflammatory drug induced damage; inflammatorydiseases of the skin such as herpes and eczema; inflammatory diseases ofthe bladder such as cystitis and urge incontinence; and eye and dentalinflammation.

Compounds of the invention are also useful in the treatment of allergicdisorders, in particular allergic disorders of the skin such asurticaria, and allergic disorders of the airways such as rhinitis.

Compounds of the invention are also useful in the treatment of emesis,i.e. nausea, retching and vomiting. Emesis includes acute emesis,delayed emesis and anticipatory emesis. The compounds of the inventionare useful in the treatment of emesis however induced. For example,emesis may be induced by drugs such as cancer chemotherapeutic agentssuch as alkylating agents, e.g. cyclophosphamide, carmustine, lomustineand chlorambucil; cytotoxic antibiotics, e.g. dactinomycin, doxorubicin,mitomycin-C and bleomycin; anti-metabolites, e.g. cytarabine,methotrexate and 5-fluorouracil; vinca alkaloids, e.g. etoposide,vinblastine and vincristine; and others such as cisplatin, dacarbazine,procarbazine and hydroxyurea; and combinations thereof; radiationsickness; radiation therapy, e.g. irradiation of the thorax or abdomen,such as in the treatment of cancer; poisons; toxins such as toxinscaused by metabolic disorders or by infection, e.g. gastritis, orreleased during bacterial or viral gastrointestinal infection;pregnancy; vestibular disorders, such as motion sickness, vertigo,dizziness and Meniere's disease; post-operative sickness;gastrointestinal obstruction; reduced gastrointestinal motility;visceral pain, e.g. myocardial infarction or peritonitis; migraine;increased intercranial pressure; decreased intercranial pressure (e.g.altitude sickness); opioid analgesics, such as morphine; andgastro-oesophageal reflux disease, acid indigestion, over-indulgence offood or drink, acid stomach, sour stomach, waterbrash/regurgitation,heartburn, such as episodic heartburn, nocturnal heartburn, andmeal-induced heartburn and dyspepsia.

Compounds of the invention are also useful in the treatment ofgastrointestinal disorders such as irritable bowel syndrome; skindisorders such as psoriasis, pruritis and sunburn; vasospastic diseasessuch as angina, vascular headache and Reynaud's disease; cerebralischeamia such as cerebral vasospasm following subarachnoid haemorrhage;fibrosing and collagen diseases such as scleroderma and eosinophilicfascioliasis; disorders related to immune enhancement or suppressionsuch as systemic lupus erythematosus and rheumatic diseases such asfibrositis; and cough.

Compounds of the invention are of particular use in the treatment ofdepressive states, in the treatment of anxiety and of panic disorders.Depressive states include major depressive disorders including bipolardepression, unipolar depression, single or recurrent major depressiveepisodes with or without psychotic features, catatonic features,melancholic features, atypical features or postpartum onset, dysthymicdisorder with early or late onset and with or without atypical features,neurotic depression and social phobia; dementia of the Alzheimer's type,with early or late onset, with depressed mood; vascular dementia withdepressed mood; mood disorders induced by alcohol, amphetamines,cocaine, hallucinogens, inhalants, opioids, phencyclidine, sedatives,hypnotics, anxiolytics and other substances; schizoaffective disorder ofthe depressed type.

Compounds of the invention may be administered in combination with otheractive substances such as 5HT3 antagonists, serotonin agonists,selective serotonin reuptake inhibitors (SSRI), noradrenaline re-uptakeinhibitors (SNRI), tricyclic antidepressants or dopaminergicantidepressants.

Suitable 5HT3 antagonists which may be used in combination of thecompounds of the inventions include for example ondansetron,granisetron, metoclopramide.

Suitable serotonin agonists which may be used in combination with thecompounds of the invention include sumatriptan, rauwolscine, yohimbine,metoclopramide.

Suitable SSRI which may be used in combination with the compounds of theinvention include fluoxetine, citalopram, femoxetine, fluvoxamine,paroxetine, indalpine, sertraline, zimeldine.

Suitable SNRI which may be used in combination with the compounds of theinvention include venlafaxine and reboxetine.

Suitable tricyclic antidepressants which may be used in combination witha compound of the invention include imipramine, amitriptiline,chlomipramine and nortriptiline.

Suitable dopaminergic antidepressants which may be used in combinationwith a compound of the invention include bupropion and amineptine.

It will be appreciated that the compounds of the combination orcomposition may be administered simultaneously (either in the same ordifferent pharmaceutical formulations) or sequentially.

The invention therefore provides a compound of formula (I) or apharmaceutically acceptable salt or solvate thereof for use in therapy,in particular in human medicine.

There is also provided as a further aspect of the invention the use of acompound of formula (I) or a pharmaceutically acceptable salt or solvatethereof in the preparation of a medicament for use in the treatment ofconditions mediated by tachykinins, including substance P and otherneurokinins.

In an alternative or further aspect there is provided a method for thetreatment of a mammal, including man, in particular in the treatment ofconditions mediated by tachykinins, including substance P and otherneurokinins, comprising administration of an effective amount of acompound of formula (I) or a pharmaceutically acceptable salt thereof.

It will be appreciated that reference to treatment is intended toinclude prophylaxis as well as the alleviation of established symptoms.

Compounds of formula (I) may be administered as the raw chemical but theactive ingredient is preferably presented as a pharmaceuticalformulation.

Accordingly, the invention also provides a pharmaceutical compositionwhich comprises at least one compound of formula (I) or apharmaceutically acceptable salt thereof and formulated foradministration by any convenient route. Such compositions are preferablyin a form adapted for use in medicine, in particular human medicine, andcan conveniently be formulated in a conventional manner using one ormore pharmaceutically acceptable carriers or excipients.

Thus compounds of formula (I) may be formulated for oral, buccal,parenteral, topical (including ophthalmic and nasal), depot or rectaladministration or in a form suitable for administration by inhalation orinsufflation (either through the mouth or nose).

For oral administration, the pharmaceutical compositions may take theform of, for example, tablets or capsules prepared by conventional meanswith pharmaceutically acceptable excipients such as binding agents (e.g.pregelatinised maize starch, polyvinylpyrrolidone or hydroxypropylmethylcellulose); fillers (e.g. lactose, microcrystalline cellulose orcalcium hydrogen phosphate); lubricants (e.g. magnesium stearate, talcor silica); disintegrants (e.g. potato starch or sodium starchglycollate); or wetting agents (e.g. sodium lauryl sulphate). Thetablets may be coated by methods well known in the art. Liquidpreparations for oral administration may take the form of, for example,solutions, syrups or suspensions, or they may be presented as a dryproduct for constitution with water or other suitable vehicle beforeuse. Such liquid preparations may be prepared by conventional means withpharmaceutically acceptable additives such as suspending agents (e.g.sorbitol syrup, cellulose derivatives or hydrogenated edible fats);emulsifying agents (e.g. lecithin or acacia); non-aqueous vehicles (e.g.almond oil, oily esters, ethyl alcohol or fractionated vegetable oils);and preservatives (e.g. methyl or propyl-p-hydroxybenzoates or sorbicacid). The preparations may also contain buffer salts, flavouring,colouring and sweetening agents as appropriate.

Preparations for oral administration may be suitably formulated to givecontrolled release of the active compound.

For buccal administration the composition may take the form of tabletsor formulated in conventional manner.

The compounds of the invention may be formulated for parenteraladministration by bolus injection or continuous infusion. Formulationsfor injection may be presented in unit dosage form e.g. in ampoules orin multi-dose containers, with an added preservative. The compositionsmay take such forms as suspensions, solutions or emulsions in oily oraqueous vehicles, and may contain formulatory agents such as suspending,stabilising and/or dispersing agents. Alternatively, the activeingredient may be in powder form for constitution with a suitablevehicle, e.g. sterile pyrogen-free water, before use.

The compounds of the invention may be formulated for topicaladministration in the form of ointments, creams, gels, lotions,pessaries, aerosols or drops (e.g. eye, ear or nose drops). Ointmentsand creams may, for example, be formulated with an aqueous or oily basewith the addition of suitable thickening and/or gelling agents.Ointments for administration to the eye may be manufactured in a sterilemanner using sterilised components.

Lotions may be formulated with an aqueous or oily base and will ingeneral also contain one or more emulsifying agents, stabilising agents,dispersing agents, suspending agents, thickening agents, or colouringagents. Drops may be formulated with an aqueous or non-aqueous base alsocomprising one or more dispersing agents, stabilising agents,solubilising agents or suspending agents. They may also contain apreservative.

The compounds of the invention may also be formulated in rectalcompositions such as suppositories or retention enemas, e.g. containingconventional suppository bases such as cocoa butter or other glycerides.

The compounds of the invention may also be formulated as depotpreparations. Such long acting formulations may be administered byimplantation (for example subcutaneously or intramuscularly) or byintramuscular injection. Thus, for example, the compounds of theinvention may be formulated with suitable polymeric or hydrophobicmaterials (for example as an emulsion in an acceptable oil) or ionexchange resins, or as sparingly soluble derivatives, for example, as asparingly soluble salt.

For intranasal administration, the compounds of the invention may beformulated as solutions for administration via a suitable metered orunitary dose device or alternatively as a powder mix with a suitablecarrier for administration using a suitable delivery device.

A proposed dose of the compounds of the invention is 1 to about 1000 mgper day. It will be appreciated that it may be necessary to make routinevariations to the dosage, depending on the age and condition of thepatient and the precise dosage will be ultimately at the discretion ofthe attendant physician or veterinarian. The dosage will also depend onthe route of administration and the particular compound selected.

Thus for parenteral administration a daily dose will typically be in therange of 1 to about 100 mg, preferably 1 to 80 mg per day. For oraladministration a daily dose will typically be within the range 1 to 300mg e.g. 1 to 100 mg.

Compounds of formula (I), and salts and solvates thereof, may beprepared by the general methods outlined hereinafter. In the followingdescription, the groups R, R₁, R₂, R₄, R₅, R₆, R₇, R₈, R₉, R₁₀, m, n, p,q and r have the meaning as previously defined for compounds of formula(I) unless otherwise stated.

According to general process (A), a compound of formula (I) wherein R₄is hydrogen or a (CH₂)qR₇ group as defined in formula (I), provided thatwhen R₅ is a C₁₋₄ alkyl or a COR₆ group, R₅ is not in 3 position of thepiperazine ring, may be prepared by reduction of a ketopiperazine offormula (II), wherein R_(4a) is hydrogen or a suitable nitrogenprotecting group or R_(4a) is a (CH₂)qR₇ group or protecting derivativesthereof followed where necessary or desired by removal of any protectinggroup.

The reaction may be carried out using a suitable metal reducing agentsuch as a metal hydride, for example a borane hydride, or a metalhydride complex like lithium aluminum hydride, borohydride, or anorgano-metallic complex such as borane-methyl sulphide,9-borabicyclononane (9-BBN), triethylsilane, sodiumtriacetoxyborohydride, sodium cyanoborohydride. Alternatively boranesmay be produced in situ by reacting Sodium Borohydride in the presenceof Iodine, an inorganic acid (e.g. sulphoric acid) or an organic acidsuch as formic acid, trifluoroacetic, acetic acid, or methansulphonicacid

Suitable solvents for this reaction are ether (e.g. tetrahydrofuran), orhalohydrocarbon (e.g. dichloromethane) or an amide (e.g.N,N-dimethylformamide) at a temperature within the range of roomtemperature to the reflux temperature of the reaction mixture.

Compounds of formula (II) may be prepared by treating compounds offormula (III) wherein R_(4a) and R₅ have the meaning defined in formula(II)

with triphosgene in aprotic solvent such as dichloromethane and in thepresence of an organic base such triethylamine to form the intermediatecarbonyl chloride compound (IV) which may be isolated if required,followed by reaction of compound (IV) with the amine compound (V)

The reaction conveniently takes place in an aprotic solvent such as ahydrocarbon, a halohydrocarbon such as dichloromethane or an ether suchas tetrahydrofuran optionally in the presence of a base such as atertiary amine e.g. diisopropyl ethyl amine.

Compounds of formula (III) may be prepared by reduction of adihydropyrazin-2-one (VI) using a suitable metal reducing agent such assodium borohydride. Alternatively, catalytic hydrogenation may be used,for example using Palladium on Carbon catalyst in a suitable solventsuch as methanol.

Alternatively compounds of formula (III) wherein R₅ is hydrogen may beprepared by reaction of compounds of formula (VII), wherein R₁₁ is aC₁₋₄ alkyl group and X is a suitable leaving group such as halogen, i.e.bromine or iodine atom, or OSO₂CF₃,

with ethylendiamine. The reaction conveniently takes place in a suitablesolvent such as alcohol (i.e. ethanol) at an elevated temperature.

According to a further general process (B) a compound of formula (I)wherein R₄ is hydrogen or (CH₂)rCO(CH₂)pR₇ as above defined may beprepared by reacting a compound of formula (VIII)

wherein R_(4b) represents a nitrogen protecting group or R_(4b) is(CH₂)rCO(CH₂)pR₇ or a protecting group thereof, with triphosgene in anaprotic solvent such as dichloromethane or alkyl esters (e.g.ethylacetate) and in the presence of an organic base such triethylamineto form the intermediate carbonyl chloride compound (IVa) which may beisolated if required, followed by reaction of compound (IV) with theamine compound (V)

The reaction conveniently takes place in an aprotic solvent such as ahydrocarbon, a halohydrocarbon such as dichloromethane or an ether suchas tetrahydrofuran or alkyl esters (i.e. ethylacetate) optionally in thepresence of a base such as a tertiary amine e.g. diisopropyl ethyl amineor triethylamine followed by deprotection where necessary.

When R_(4a) or R_(4b) is a nitrogen protecting group, examples ofsuitable groups include alkoxycarbonyl e.g. t-butoxycarbonyl,benzyloxycarbonyl, arylsulphonyl e.g. phenysulphonyl or2-trimethylsilylethoxymethyl.

Protection and deprotection may be effected using conventionaltechniques such as those described in “Protective Groups in OrganicSynthesis 2^(nd) Ed.” by T. W. Greene and P. G. M. Wuts (John Wiley andSons, 1991) and as described in the examples hereinafter.

Compounds of formula (I) wherein R₄ is a CO(CH₂)pR₇ group or protectivederivatives thereof may be also prepared by reaction of the compound offormula (I)

wherein R₄ is a hydrogen atom, with an activated derivative of the acidR₇(CH₂)pCO₂H(IX).

The activated derivatives of the carboxylic acid (IX) may be prepared byconventional means. Suitable activated derivatives of the carboxylicgroup include the corresponding acyl halide, mixed anhydride, activatedester such as thioester or the derivative formed between the carboxylicacid group and a coupling agent such as that used in peptide chemistry,for example carbonyl diimidazole or a diimide such as1-(3-dimethylaminopropyl)-3-ethylcarbodiimide.

The reaction is preferably carried out in an aprotic solvent such as anamide e.g. N,N-dimethylformamide or acetonitrile.

Compounds of formula (I) wherein R₄ is CONR₉R₈ in which R₉ or R₈ havethe meaning defined in formula (I) may be prepared by reaction of acompound of formula (I) wherein R₄ is a hydrogen atom with triphosgenein an aprotic solvent such as dichloromethane and in the presence of anorganic base such as triethylamine followed by reaction with the aminecompound NR₉R₈(X).

Alternatively compounds of formula (I) wherein R₄ is a CONHR₉ group inwhich R₉ is C₁₋₄ alkyl may be also prepared by reaction with isocyanateof formula R₉NC═O (XI). The reaction with the compound (XI) isconveniently carried out in a solvent such as tetrahydrofuran or aqueoustetrahydrofuran, a halohydrocarbon (e.g. dichloromethane) oracetonitrile optionally in the presence of a base such as triethylamineand at temperature within the range 0-80° C.

In a further embodiment compounds of formula (I) wherein R₄ is (CH₂)qR₇or R₄ is (CH₂)rCO(CH₂)pR₇ wherein q, r and R₇ have the meanings definedin formula (I) or are protective derivatives thereof with the provisionthat r is not zero, may also be prepared by reaction of compounds offormula (I) wherein R₄ is a hydrogen group with a compound of formula(XII) R₇(CH₂)qX or X(CH₂)rCO(CH₂)pR₇ (XIII), in which X is a leavinggroup such as halogen e.g. chlorine, a bromine atom, a mesyl or a tosylgroup.

In a further preferred embodiment compounds of formula (I) wherein R₄ is(CH₂)qR₇ wherein q and R₇ have the meanings defined in formula (I) orare protective derivatives thereof may be also prepared by reaction ofcompounds of formula (I) wherein R₄ is a hydrogen group with a compoundof formula (XIV) R₇(CH₂)qCHO (XIV), in which q is zero or an integerfrom 1 to 3 and R₇ has the meanings defined in formula (I) or areprotective derivatives thereof, in the presence of suitable metalreducing agent such as NaCNBH₃.

In a further preferred embodiment compounds of formula (I) wherein R₁and R₂ together with nitrogen and carbon atom to which they are attachedrespectively represent a 5 to 6 unsaturated membered heterocyclic groupmay be prepared by ring closing metathesis reaction (RCM) of compoundsof formula (XV).

catalysed by a transition metal complex such as a ruthenium alkylidenecomplex (i.e. benzylidene bis(tricyclohexylphosphine)dichlororuthenium).The reaction is conveniently carried out in an aprotic solvent suchdichloromethane at 0° C.

Compounds of formula (XV) may be prepared from the appropriateintermediate using any of the processes described herein for preparingcompounds of formula (I).

Compound of formula (I) wherein R₁ and R₂ together with nitrogen andcarbon atom to which they are attached respectively represent a 5 to 6saturated membered heterocyclic group may be prepared by reduction ofthe corresponding 5 to 6 unsaturated membered heterocyclic group withsuitable reducing agent such as catalytic hydrogenation in a suitablesolvent such as methanol at room temperature.

Where it is desired to isolate a compound of formula (I) as a salt, forexample a pharmaceutically acceptable salt, this may be achieved byreacting the compound of formula (I) in the form of the free base withan appropriate amount of suitable acid and in a suitable solvent such asan alcohol (e.g. ethanol or methanol), an ester (e.g. ethyl acetate) oran ether (e.g. diethyl ether tertbutylmethyl ether or tetrahydrofuran).

Compounds of formula (V), (VI), (VIII), (IX), (X), (XII), (XIII) or(XIV) may be prepared by analogous methods to those used for knowncompounds.

Thus for example compounds of formula (VIII) may be obtained byreduction of a compound of formula (III).

The reaction may be carried out using a suitable metal reducing agentsuch as a metal hydride, for example a borane hydride, or a metalhydride complex like lithium aluminum hydride, borohydride, or anorgano-metallic complex such as borane-methyl sulphide,9-borabicyclononane (9-BBN), triethylsilane, sodiumtriacetoxyborohydride, sodium cyanoborohydride. Alternatively boranesmay be produced in situ by reacting Sodium Borohydride in the presenceof Iodine, an inorganic acid (e.g. sulphoric) or an organic acid such asformic acid, trifluoroacetic, acetic acid, methansuphonic acid

Pharmaceutically acceptable salts may also be prepared from other salts,including other pharmaceutically acceptable salts, of the compound offormula (I) using conventional methods.

The compounds of formula (I) may readily be isolated in association withsolvent molecules by crystallisation from or evaporation of anappropriate solvent to give the corresponding solvates.

When a specific enantiomer of a compound of general formula (I) isrequired, this may be obtained for example by resolution of acorresponding enantiomeric mixture of a compound of formula (I) usingconventional methods.

Thus specific enantiomers of the compounds of formula (I) in which R₄ isa hydrogen atom may be prepared by reaction of a suitable chiralalcohol, in the presence of a source of a carbonyl group (such astriphosgene or carbonyl diimidazole) separating the resultingdiastereoisomeric carbamates by conventional means e.g. chromatographyor by fractional crystallisation. The required enantiomer of a compoundof general formula (I) may be isolated by removal of carbamate andconversion into the required free base or salts thereof.

Suitable chiral alcohols for use in the process include(R)-sec-phenylethyl alcohol, etc.

Alternatively, enantiomers of a compound of general formula (I) may besynthesised from the appropriate optically active intermediates usingany of the general processes described herein.

Thus for example the required enantiomer may be prepared by thecorresponding enantiomeric amine of formula (III) using any of theprocesses described above for preparing compounds of formula (I) fromthe amine (III). The enantiomer of amine (III) may be prepared from theracemic amine (III) using conventional procedures such as salt formationwith a suitable optically active acid such as L(+)mandelic acid or(1S)-(+)-10-camphorsulfonic acid

In one preferred embodiment of the invention the specific enantiomer ofamine (IIIa)

may be prepared by dynamic kinetic resolution of amine(III) with asuitable optically active acid such as L(+)mandelic acid or(1S)-(+)-10-camphorsulfonic acid in the presence of aromatic aldehydesuch as 3,5 dichlorosalicylaldhyde, salicylaldhyde, benzaldehyde-p-nitrobenzaldehyde.

A particular preferred aldehyde for use in this reaction is 3,5dichlorosalicylaldhyde.

The reaction is conveniently carried out in an aprotic solvent such astetrahydrofuran, ethyl actetate at a temperature ranging between 20-60°C.

The invention is further illustrated by the following Intermediates andExamples which are not intended as a limitation of the invention.

In the Intermediates and Examples unless otherwise stated:

Melting points (m.p.) were determined on a Gallenkamp m.p. apparatus andare uncorrected. All temperatures refers to ° C. Infrared spectra weremeasured on a FT-IR instrument. Proton Magnetic Resonance (¹H-NMR)spectra were recorded at 400 MHz, chemical shifts are reported in ppmdownfield (d) from Me₄Si, used as internal standard, and are assigned assinglets (s), doublets (d), doublets of doublets (dd), triplets (t),quartets (q) or multiplets (m). Column chromathography was carried outover silica gel (Merck AG Darmstaadt, Germany). The followingabbreviations are used in text: AcOEt=ethyl acetate, CH=cyclohexane,DCM=dichloromethane, Et₂O=dietyl ether, DMF=N,N′-dimethylformamide,DIPEA=N,N-diisopropylethylamine MeOH=methanol, TEA=triethylamine,TFA=trifluoroacetic acid, THF=tetrahydrofuran. Tlc refers to thin layerchromatography on silica plates, and dried refers to a solution driedover anhydrous sodium sulphate; r.t. (RT) refers to room temperature.

Enantiomer A or enantiomer B refer to a single enantiomer whose absolutestereochemistry was not characterised.

Diastereoisomer A refers to a mixture of compounds having anticonfiguration as defined above.

Diastereoisomer B refers to a mixture of compounds having synconfiguration as defined above.

Intermediate 1 2-Methyl-4-fluoroboronic acid

To magnesium turnings (0.5 g), heated at 90° C., a solution ofcommercial 2-bromo-5-fluorotoluene (2 mL) in THF (3 mL) was addeddrop-wise. The reaction mixture was heated at 90-95° C. for 1½ hr, andthen the mixture was diluted with further THF (10 mL) and transferred ina dropping funnel. The latter solution and trimethylborate (2.1 mL) weresimultaneously added to stirred Et₂O (15 mL), maintaining thetemperature below −60° C. The reaction mixture was allowed to warm tor.t., then the stirring was continued for 1½ hr. Water (6 mL) was addedand the reaction mixture was stirred overnight. AcOEt was added and thesolution was washed with 1N HCl and brine. The organic phase was nextdried and concentrated to give the crude product which was triturated inEt₂O/petroleum (25 mL/75 mL) to obtain the title compound as a trimer(1.44 g, white powder).

NMR (DMSO) δ (ppm) 7.87 (m, 3H), 6.99-6.93 (m, 6H), 2.6 (s, 9H)

Intermediate 2 2-(4-Fluoro-2-methyl-phenyl)-pyrazine

A mixture of intermediate 1 (1.34 g), 2-chloropyrazine (1 mL) andbis[1,2-bis(diphenylphosphino)ethane]-palladium(0) (0.21 g) intoluene/1M sol. Na₂CO₃/EtOH 95% 20 mL/20 mL/10 mL was heated at refluxfor 2 hr. The solution was poured into AcOEt and washed with brine. Theorganic phase was next dried and concentrated to give the crude product,which was purified by flash chromatography (CH/AcOEt 85:15) to obtainthe title compound (1.4 g) as a white powder.

m.p.=66-68° C.

NMR (DMSO) δ (ppm) 8.81 (d, 1H), 8.72 (m, 1H), 8.63 (d, 1H), 7.52 (m,1H), 7.22 (m, 1H), 7.17 (m, 1H), 2.35 (s, 3H).

Intermediate 3 2-(3-Isopropyl-phenyl)-pyrazine

To a solution of commercial 3-isopropyl-benzene boronic acid (1.0 g) ina 2:2:1 mixture of toluene/1M Na₂CO₃/EtOH (122 mL), at r.t.,2-chloropyrazine (599 μL) and thebis[1,2-bis(diphenylphosphino)ethane]-palladium(0) catalyst (110 mg)were added. The reaction mixture was heated at 80° C. for 3 hr. It wasthen cooled down and partitioned between AcOEt/sat.aq. NaCl. The phaseswere separated and the organic layer was dried. The solids were filteredand the solvent evaporated. The crude oil was purified by flashchromatography (CH/AcOEt 7:3) obtaining the title compound as a clearoil (468 mg).

NMR (CDCl₃): δ (ppm) 9.02 (d, 1H), 8.63 (m, 1H), 8.49 (d, 1H), 7.89 (m,1H), 7.80 (m, 1H), 7.44 (t, 1H), 7.35 (d, 1H), 3.02 (m, 1H), 1.31 (d,6H).

Intermediate 4 2-(2-isopropyl-phenyl)-pyrazine

1) To a suspension of magnesium turnings (134 mg) in anh. THF (2.5 mL),at r.t., under N₂, a small crystal of I₂ was added, followed by 10% of asolution of commercial 1-bromo-2-isopropyl-benzene (1.0 g) in anh. THF(2.6 mL). The suspension was heated gently (heat gun) until the browncolour disappeared. The remaining bromide was added drop-wise,maintaining the reaction mixture warm (50-60° C.) with an oil bath.After the addition was complete (15 min) the suspension was stirred at60° C. until the magnesium turnings had almost completely reacted (2hr). The new brown solution was used in the next step.

2) To a solution of the 2-chloropyrazine (448 μL) in anh. THF (5.1 mL),at 0° C., under N₂, [1,2-bis(diphenylphosphino)ethane]dichloronickel(II)(100 mg) and the Grignard solution were successively added drop-wise.The brown solution was stirred at r.t. for 30 min, then at reflux for 3hr. It was then poured in sat.aq. NaCl/DCM and the phases wereseparated. The aqueous layer was extracted with DCM (2×) and thecombined organic extracts were dried. The solids were filtered and thesolvent evaporated. The crude oil obtained was purified by flashchromatography (CH/AcOEt 7:3) obtaining the title compound as a yellowoil (676 mg).

NMR (CDCl₃): δ (ppm) 8.67 (d, 1H), 8.67 (m, 1H), 8.54 (d, 1H), 7.5-7.3(m, 4H), 3.13 (m, 1H), 1.20 (d, 6H).

Intermediate 5 2-(4-Fluoro-3-methyl-phenyl)-pyrazine

1) To a suspension of magnesium turnings (167 mg) in anh. THF (2.6 mL),at r.t., under N₂, a small crystal of 12 was added, followed by 10% of asolution of commercial 4-bromo-1-fluoro-2-methyl-benzene (1.0 g) in anh.THF (2.7 mL). The suspension was heated gently (heat gun) until thebrown colour disappeared. The remaining bromide was added drop-wise,maintaining the reaction mixture warm (50-60° C.) with an oil bath.After the addition was complete (15 min) the suspension was stirred at60° C. until the magnesium turnings had almost completely reacted (2hr). The new brown solution was used in the next step.

2) To a solution of the 2-chloropyrazine (472 μL) in anh. THF (5.3 mL),at 0° C., under N₂, [1,2-bis(diphenylphosphino)ethane]dichloronickel(II)(100 mg) and the Grignard solution were successively added dropwise. Thebrown solution was stirred at r.t. for 30 min, then at reflux for 3 hr.It was then poured in sat.aq. NaCl/DCM and the phases were separated.The aqueous layer was extracted with DCM (2×) and the combined organicextracts were dried. The solids were filtered and the solventevaporated. The crude oil obtained was purified by flash chromatography(CH/AcOEt 7:3) to give the title compound as a yellow oil (571 mg).

NMR (CDCl₃): δ (ppm) 8.98 (d, 1H), 8.60 (m, 1H), 8.49 (d, 1H), 7.87 (m,1H), 7.80 (m, 1H), 7.13 (t, 1H), 2.37 (s, 3H).

Intermediate 6 2-(2,4-Difluoro-phenyl)-pyrazine

1) To a suspension of magnesium turnings (139 mg) in anh. THF (2.6 mL),at r.t., under N₂, a small crystal of 12 was added, followed by 10% of asolution of commercial 1-bromo-2,4-difluoro-benzene (1.0 g) in anh. THF(2.6 mL). The suspension was heated gently (heat gun) until the browncolour disappeared. The remaining bromide was added drop-wise,maintaining the reaction mixture warm (50-60° C.) with an oil bath.After the addition was complete (15 min) the suspension was stirred at60° C. until the magnesium turnings had almost completely reacted (2hr). The new brown solution was used in the next step.

2) To a solution of the 2-chloropyrazine (463 μL) in anh. THF (5.2 mL),at 0° C., under N₂, [1,2-bis(diphenylphosphino)ethane]dichloronickel(II)(50 mg) and the Grignard solution were successively added drop-wise. Thebrown solution was stirred at r.t. for 30 min, then at reflux for 3 hr.It was then poured in sat.aq. NaCl/DCM and the phases were separated.The aqueous layer was extracted with DCM (2×) and the combined organicextracts were dried. The solids were filtered and the solventevaporated. The crude oil obtained was purified by flash chromatography(CH/AcOEt 7:3) to give the title compound as a yellow solid (175 mg).

NMR (CDCl₃): δ (ppm) 9.01 (dd, 1H), 8.78 (dd, 1H), 8.66 (d, 1H), 7.99(td, 1H), 7.47 (td, 1H), 7.29 (td, 1H).

Intermediate 7 2-(4-Fluoro-2-methyl-phenyl)-piperazine hydrochloride

A two neck round bottom flask was equipped with a water condenser and adropping funnel and was flushed with N₂. Mg turnings (1.45 g) wereintroduced in the flask and were suspended in anh. THF (5 mL). A smallcrystal of 12 was added in order to activate the Mg. The dropping funnelwas filled with a solution of the commercial 2-bromo-5-fluorotoluene (10g) in anh. THF (30 mL). The solution of the bromide was added drop-wiseto the Mg turnings and the solution warmed up to approximately 70° C.The solution was kept at that temperature until complete disappearanceof the Mg turnings.

Meanwhile, 2-chloropyrazine (4.75 mL) was dissolved in anh. THF (30 mL)and [1,2-bis(diphenylphosphino)ethane]dichloronickel(II) (510 mg) wasadded. To this suspension the solution of Grignard was added dropwise,at 0° C., under N₂. After the addition was complete, the reactionmixture was heated at reflux for 2 hr. The THF was evaporated, theresidue poured in sat. aq. NaCl and the aqueous phase was extracted withDCM (3×). The organic extracts were dried, the solids were filtered andthe solvent evaporated. The crude oil was purified by flashchromatography (CH/AcOEt 85:15) and then through a small column ofFlorisil (eluant: DCM) to eliminate the nickel residue (6.0 g):2-(4-fluoro-2-methyl-phenyl)-pyrazine (6.0 g) was obtained as a paleyellow solid. 2-(4-Fluoro-2-methyl-phenyl)-pyrazine (0.3 g) dissolved inEtOH 95% (20 mL) and 37% HCl (0.2 mL) was hydrogenated at 5 atm. for 4hr, in the presence of 20% Pd(OH)₂/C (30 mg) as catalyst. The catalystwas filtered off and the solvent was evaporated. The crude residue wastriturated in MeOH/AcOEt (5 mL/15 mL) to obtain the title compound (0.08g) as a white powder.

m.p.>220° C.

NMR (DMSO) δ (ppm) 9.72 (broad, 2H), 7.90 (d, 1H), 7.21-7.17 (m, 2H),4.85 (m, 1H), 3.57-3.2 (m, 6H), 2.40 (s, 3H).

Intermediate 8 3-(4-Fluoro-2-methyl-phenyl)-piperazine-1-carboxylic acidbenzyl ester

To a solution of intermediate 7 (0.25 g) and TEA (0.5 mL) in DCM (15 mL)a solution of benzylchloroformate (0.15 mL) in DCM (10 mL) was addeddrop-wise, at 0° C. The reaction mixture was stirred at 0° C. for 2 hr,then washed with brine. The organic phase was dried and concentrated togive the crude product, which was purified by flash columnchromatography (CH/AcOEt 25:75) to obtain the title compound (0.21 g) asa colourless oil.

NMR (CDCl₃, 40° C.) δ (ppm) 7.52 (m, 1H), 7.4-7.3 (m, 5H), 6.9-6.8 (m,2H), 5.16 (dd, 2H), 4.12 (m, 2H), 3.86 (m, 1H), 3.3-2.7 (m, 4H), 2.33,(bs, 3H).

Intermediate 9 3-(3-Isopropyl-phenyl)-piperazine-1-carboxylic acidbenzyl ester

To a solution of intermediate 3 (428 mg) in anh. EtOH (47 mL), at r.t.,under N₂, conc. HCl (492 μL) and Pd(OH)₂/C 20% (86 mg, 20% wt) wereadded. The black suspension was placed in a PARR apparatus and thehydrogenation was done at r.t. under 7 atm of H₂ for 18 hr. The catalystwas then filtered on Celite and the Celite cake rinsed with MeOH. Thefiltrate was evaporated to dryness. The grey solid2-(3-Isopropyl-phenyl)-piperazine hydrochloride (654 mg) was dissolvedin anh. DCM (24 mL), at 0° C., under N₂, then TEA (1.32 mL) andbenzylchloroformate (404 μL) were added. The solution was stirred at 0°C. for 2½ hr. It was then poured in DCM/sat.aq. NaCl/sat.aq. K₂CO₃ andthe phases were separated. The aqueous layer was extracted with DCM (1×)and the combined organic extracts were dried. The solids were filteredand the solvent evaporated. The crude oil was purified by flashchromatography (CH/AcOEt 6:4) to give the title compound as a yellow oil(192 mg).

NMR (CDCl₃): δ (ppm) 7.34-7.12 (m, 8H), 5.08 (m, 2H), 3.89 (bd, 1H),3.85 (bm, 1H), 3.55 (bd, 1H), 3.0-2.65 (bm, 6H), 1.17 (d, 6H).

Intermediate 10 3-(2-Isopropyl-phenyl)-piperazine-1-carboxylic acidbenzyl ester

To a solution of intermediate 4 (315 mg) in anh. EtOH (40 mL), at r.t.,under N₂, conc. HCl (529 μL) and Pd(OH)₂/C 20% (63 mg, 20% wt) wereadded. The black suspension was placed in a PARR apparatus and thehydrogenation was done at r.t. under 7 atm of H₂ for 18 hr. The catalystwas then filtered on Celite and the Celite cake rinsed with MeOH. Thefiltrate was evaporated to dryness. The grey solid2-(2-Isopropyl-phenyl)-piperazine hydrochloride (411 mg) was dissolvedin anh. DCM (16 mL), at 0° C., under N₂, then TEA (886 μL) andbenzylchloroformate (272 μL) were added. The solution was stirred at 0°C. for 2.5 hr. It was then poured in DCM/sat.aq. NaCl/sat.aq. K₂CO₃ andthe phases were separated. The aqueous layer was extracted with DCM (1×)and the combined organic extracts were dried. The solids were filteredand the solvent evaporated. The crude oil was purified by flashchromatography (CH/AcOEt 6:4) obtaining the title compound as a yellowoil (117 mg).

NMR (CDCl₃): δ (ppm) 7.52 (d, 1H), 7.4-7.3 (m, 5H), 7.26 (d, 1H), 7.21(t, 1H), 7.14 (t, 1H), 5.14 (d, 1H), 5.03 (d, 1H), 4.0-3.8 (m, 3H), 3.23(m, 1H), 2.99 (m, 1H), 2.91 (m, 1H), 2.8-2.0 (m, 2H), 1.19 (d, 6H).

Intermediate 11 3-(4-Fluoro-3-methyl-phenyl)-piperazine-1-carboxylicacid benzyl ester

To a solution of intermediate 5 (314 mg) in anh. EtOH (30 mL), at r.t.,under N₂, conc. HCl (350 μL) and Pd(OH)₂/C 20% (30 mg, 10% wt) wereadded. The black suspension was placed in a PARR apparatus and thehydrogenation was done at r.t. under 7 atm of H₂ for 18 hr. The catalystwas then filtered on Celite and the Celite cake rinsed with MeOH. Thefiltrate was evaporated to dryness. The grey solid2-(4-Fluoro-3-methyl-phenyl)-piperazine hydrochloride (411 mg) wasdissolved in anh. DCM (15 mL), at 0° C., under N₂, then TEA (858 μL) andbenzylchloroformate (264 μL) were added. The solution was stirred at 0°C. for 2.5 hr. It was then poured in DCM/sat.aq. NaCl/sat.aq. K₂CO₃ andthe phases were separated. The aqueous layer was extracted with DCM (1×)and the combined organic extracts were dried. The solids were filteredand the solvent evaporated. The crude oil was purified by flashchromatography (CH/AcOEt 6:4) obtaining the title compound as a yellowoil (170 mg).

NMR (CDCl₃): δ (ppm) 7.3-7.4 (m, 5H), 7.23 (m, 1H), 7.17 (m, 1H), 6.96(t, 1H), 5.17 (m, 2H), 4.15 (m, 2H), 3.67 (m, 1H), 2.7-3.2 (m, 4H), 2.27(s, 3H).

Intermediate 12 3-(2,4-Difluoro-phenyl)-piperazine-1-carboxylic acidbenzyl ester

To a solution of intermediate 6 (175 mg) in anh. EtOH (30 mL), at r.t.,under N₂, conc. HCl (228 μL, 2.5 eq) and Pd(OH)₂/C 20% (20 mg, 10% wt)were added. The black suspension was placed in a PARR apparatus and thehydrogenation was done at r.t. under 7 atm of H₂ for 18 hr. The catalystwas then filtered on Celite and the Celite cake rinsed with MeOH. Thefiltrate was evaporated to dryness. The greenish solid2-(2,4-Difluoro-phenyl)-piperazine hydrochloride (247 mg) was dissolvedin anh. DCM (9.1 mL), at 0° C., under N₂, then TEA (508 μL) andbenzylchloroformate (162 μL) were added. The solution was stirred at 0°C. for 3 hr. It was then poured in DCM/sat.aq. NaCl/sat.aq. K₂CO₃ andthe phases were separated. The aqueous layer was extracted with DCM (1×)and the combined organic extracts were dried. The solids were filteredand the solvent evaporated. The crude oil was purified by flashchromatography (CH/AcOEt 6:4) obtaining the title compound as a yellowoil (100 mg).

NMR (CDCl₃): δ (ppm) 7.49 (m, 1H), 7.3-7.4 (m, 5H), 6.76-6.8 (m, 2H),5.16 (s, 2H), 4.15 (m, 2H), 4.03 (m, 1H), 2.8-3.15 (m, 4H).

Intermediate 134-[(3,5-Bis-trifluoromethyl-benzyl)-methyl-carbamoyl]-3-(4-fluoro-2-methyl-phenyl)-piperazine-1-carboxylicacid benzyl ester

A solution of triphosgene (0.02 mL) in DCM (10 mL) was added drop-wiseto a solution of intermediate 8 (0.05 g) and TEA (0.15 mL) in DCM (10mL) at 0° C. The reaction mixture was allowed to warm to r.t. in 3 hr,then DIPEA (0.07 mL) and (3,5-bis-trifluoromethyl-benzyl)-methyl-aminehydrochloride (53 mg) were added. The reaction mixture was stirred atreflux for 2 hr and at r.t. overnight, then was washed with a 1Nsolution of HCl and brine. The organic phase was dried and concentratedto give the crude product, which was purified by flash chromatography(CH/AcOEt 7:3) to obtain the title compound (0.05 g) as a colourlessoil.

NMR (CDCl₃) δ (ppm) 7.76 (s, 1H), 7.49 (s, 2H), 7.4-7.3 (m, 5H), 7.20(dd, 1H), 6.86 (d, 1H), 6.79 (m, 1H), 5.17 (s, 2H), 4.66 (d, 1H), 4.64(m, 1H), 4.36 (d, 1H), 3.97 (m, 2H), 3.4 (m, 2H), 3.16 (m, 2H), 2.93 (s,3H), 2.38 (bs, 3H).

Intermediate 144-[(3,5-Bis-trifluoromethyl-benzyl)-methyl-carbamoyl]-3-(3-isopropyl-phenyl)piperazine-1-carboxylicacid benzyl ester

To a solution of intermediate 9 (192 mg) in anh. DCM (7 mL), at 0° C.,under N₂, TEA (237 μL) was added. Then, a solution of triphosgene (76mg) in anh. DCM (4 mL) was added drop-wise. The reaction was stirred at0° C. for 2 hr.

To this solution DIPEA (198 μL) and(3,5-bis-trifluoromethyl-benzyl)-methyl-amine hydrochloride (200 mg)were added. The solution was stirred at r.t. for 18 hr. The reactionmixture was diluted with DCM, washed with 10% citric acid (1×) anddried. The solids were filtered and the solvent evaporated. The crudeoil was purified by flash chromatography (CH/AcOEt 65:35) to give thetitle compound as a thick oil (353 mg).

NMR (CDCl₃): δ (ppm) 7.91 (bs, 1H), 7.84 (bs 2H), 7.36-7.26 (m, 5H),7.18-7.10 (m, 2H), 7.06 (m, 2H), 5.07 (s, 2H), 4.76 (t, 1H), 4.50 (bs,2H), 3.96 (dd, 1H), 3.66 (td, 1H), 3.57 (dd, 1H), 3.4-3.3 (m, 2H), 3.19(m, 1H), 2.86 (s, 3H), 2.76 (m, 1H), 1.09 (2d, 6H).

Intermediate 154-[(3,5-Bis-trifluoromethyl-benzyl)-methyl-carbamoyl]-3-(2-isopropyl-phenyl)-piperazine-1-carboxylicacid benzyl ester

To a solution of intermediate 10 (46 mg) in anh. DCM (3.9 mL), at 0° C.,under N₂, TEA (145 μL) was added. then a solution of triphosgene (46 mg)in anh. DCM (3 mL) was added drop-wise. The reaction was stirred at 0°C. for 2 hr.

To this solution, DIPEA (121 μL) and(3,5-bis-trifluoromethyl-benzyl)-methyl-amine hydrochloride (122 mg)were added. The solution was stirred at r.t. for 18 hr. The reactionmixture was diluted with DCM, washed with 10% citric acid (1×) anddried. The solids were filtered and the solvent evaporated. The crudeoil was purified by flash chromatography (CH/AcOEt 7:3) to give thetitle compound as a clear oil (108 mg).

NMR (CDCl₃): δ (ppm) 7.89 (bs, 1H), 7.71 (bs, 2H), 7.38-7.28 (m, 5H),7.28 (dd, 1H), 7.23 (dd, 1H), 7.16 (dt, 1H), 7.01 (dt, 1H), 5.14 (d,1H), 5.05 (bd, 1H), 4.68 (dd, 1H), 4.52 (2d(AB), 2H), 3.83 (dd, 1H),3.71 (dt, 1H), 3.53 (md, 1H), 3.41 (dt, 1H), 3.26 (m, 1H), 3.15-3.05 (m,2H), 1.19 (d, 3H), 1.13 (m, 3H).

Intermediate 164-[(3,5-Bis-trifluoromethyl-benzyl)-methyl-carbamoyl]-3-(4-fluoro-3-methyl-phenyl)-piperazine-1-carboxylicacid benzyl ester

To a solution of intermediate 11 (170 mg) in anh. DCM (7 mL), at 0° C.,under N₂, TEA (217 μL) was added. Then, a solution of triphosgene (69mg) in anh. DCM (3 mL) was added drop-wise. The reaction was stirred at0° C. for 2 hr.

To this solution DIPEA (181 μL) and(3,5-bis-trifluoromethyl-benzyl)-methyl-amine hydrochloride (183 mg)were added. The solution was stirred at r.t. for 18 hr. The reactionmixture was diluted with DCM, washed with 10% citric acid (1×) anddried. The solids were filtered and the solvent evaporated. The crudeoil was purified by flash chromatography (CH/AcOEt 65:35) to give thetitle compound as a gummy solid (226 mg).

NMR (CDCl₃): δ (ppm) 7.77 (m, 1H), 7.60 (m, 2H), 7.3-7.4 (m, 5H),7.05-7.15 (m, 2H), 6.90 (m, 1H), 5.14 (m, 2H), 4.6-4.8 (m, 1H),4.54+4.47 (AB, 2H), 3.82 (bm, 1H), 3.73 (dd, 1H), 3.65 (m, 1H), 3.57 (m,1H), 3.33 (m, 1H), 3.26 (m, 1H), 2.90 (s, 3H), 2.19 (s, 3H).

Intermediate 174-[(3,5-Bis-trifluoromethyl-benzyl)-methyl-carbamoyl]-3-(2,4-difluoro-phenyl)-piperazine-1-carboxylicacid benzyl ester

To a solution of intermediate 12 (95 mg) in anh. DCM (3 mL), at 0° C.,under N₂, TEA (120 μL) was added. Then a solution of triphosgene (38 mg)in anh. DCM (3 mL) was added dropwise. The reaction was stirred at 0° C.for 2 hr.

To this solution DIPEA (100 μL, 2 eq) and(3,5-bis-trifluoromethyl-benzyl)-methyl-amine hydrochloride (101 mg)were added. The solution was stirred at r.t. for 18 hr. The reactionmixture was diluted with DCM, washed with 10% citric acid (1×) anddried. The solids were filtered and the solvent evaporated. The crudeoil was purified by flash chromatography (CH/AcOEt 7:3) to give thetitle compound as a yellow gum (134 mg).

NMR (CDCl₃): δ (ppm) 7.76 (s, 1H), 7.56 (s, 2H), 7.26-7.40 (m, 6H), 6.76(m, 2H), 5.17 (m, 2H), 4.83 (m, 1H), 4.36-4.60 (dd+m, 2H), 3.90 (m, 1H),3.25-3.7 (m, 2H), 2.86 (s, 3H).

Intermediate 184-(3,5-Bis-trifluoromethyl-benzyl-carbamoyl)-3-(4-fluoro-2-methyl-phenyl)-piperazine-1-carboxylicacid benzyl ester

To a solution of intermediate 8 (0.15 g) and TEA (0.32 ml) in DCM (35ml), a solution of triphosgene (0.065 ml) in DCM (25 ml) was addeddrop-wise at 0° C. The reaction mixture was allowed to warm to r.t. in 3hr, then pyridine (0.3 mL) and3,5-bis(trifluoromethyl)-benzyl-1-methyl-amine hydrochloride (53 mg)were added. The reaction mixture was stirred at r.t. overnight, thenwashed with a 1N solution of HCl and brine. The organic phase was nextdried and concentrated to give the crude product which was purified byflash chromatography (CH/AcOEt 7:3) to obtain the title compound (0.086g) as a pale yellow oil and4-benzyloxycarbonyl-2-(4-fluoro-2-methyl-phenyl)-piperazine-1-carbonylchloride (0.075 g).

Title compound: NMR (CDCl₃) δ (ppm) 7.8-7.7 (m, 1H), 7.5-7.4 (m, 2H),7.4-7.25 (m, 5H), 7.20 (m, 1H), 6.95-6.8 (m, 2H), 5.2-5.05 (m, 2H), 4.99(dd, 1H), 4.6-4.2 (m, 2H), 4.5-4.15 (m, 2H), 3.8-3.6 (m, 2H), 4.12 (m,1/2H), 3.91 (m, 1/2H), 3.61 (m, 1/2H), 3.44 (m, 1/2H), 2.4-2.2 (s+s,3H).

Intermediate 19 3-(4-Fluoro-2-methyl-phenyl)-piperazine-1-carboxylicacid 1-(S)-phenyl-ethyl ester

To a solution of 1,1′carbonyldiimidazole (0.162 g) in DCM (5 mL)(S)-sec-phenethyl alcohol (0.122 g) was added. After 30 min. a solutionof intermediate 7 (0.180 g) in acetonitrile (5 mL) was added and themixture refluxed for 2 hr. Then the mixture was concentrated to give thecrude product, which was purified by flash chromatography (CH/AcOEt 8:2)to give the title compound (mix diastereomers) (0.180 g) as a foam.

NMR (DMSO) δ (ppm) 7.87 (m, 1H); 7.40-7.25 (m, 5H); 7.02-6.94 (m, 2H);5.74 (m, 1H); 3.93-3.71 (m, 3H); 3.00-2.55 (m, 4H); 2.34 (s, 3H); 2.28(s, 3H)

Intermediate 204-(3,5-Bis-trifluoromethyl-benzyl-carbamoyl)-3-(R)-(4-fluoro-2-methyl-phenyl)-piperazine-1-carboxylicacid 1-(S)-phenyl-ethyl ester (diastereomer 1) (20a)4-(3,5-Bis-trifluoromethyl-benzyl-carbamoyl)-3-(S)-(4-fluoro-2-methyl-phenyl)-piperazine-1-carboxylicacid 1-(S)-phenyl-ethyl ester (diastereomer 2) (20b)

A solution of triphosgene (0.075 g) in DCM (5 mL) was added drop-wise toa solution of intermediate 19 (0.180 g) and TEA (0.35 mL) in DCM (5 mL)at 0° C. After 2 hr, DIPEA (0.3 mL) and(3,5-bistrifluoromethylbenzyl)-methyl-amine hydrochloride (0.209 g) wereadded and the mixture was warmed at r.t. After 4 hr, DCM was added andthe organic phase was washed with HCl 1N (2×10 mL) and brine, dried andconcentrated to give the crude diastereisomeric mixture. Separation byflash chromatography (CH/AcOEt 8:2) yielded the title compound 20a(0.125 g) and the title compound 20b (0.135 g) as white foams.

Intermediate 20a: NMR (DMSO) δ (ppm) 7.90 (s, 1H); 7.67 (s, 2H);7.4-7.27 (m, 6H); 6.95 (dd, 1H); 6.80 (m, 1H); 5.74 (q, 1H); 4.60-4.40(dd, 2H); 4.50 (m, 1H); 3.79 (m, 3H); 3.00 (m, 3H); 2.87 (s, 3H); 2.29(s, 3H); 1.46 (d, 3H).

Intermediate 20b: NMR (DMSO) δ (ppm) 7.90 (s, 1H); 7.67 (s, 2H);7.37-7.24 (m, 6H); 6.95 (dd, 1H); 6.81 (m, 1H); 5.75 (q, 1H); 4.60-4.41(dd, 2H); 4.52 (m, 1H); 3.83-3.00 (m, 6H); 2.88 (s, 3H); 2.33 (s, 3H);1.48 (d, 3H).

Intermediate 21 [1-(2,4-Bis-trifluoromethyl-phenyl)-ethyl]-methyl-amine

To a 2 M solution of MeNH₂ in MeOH (10 mL) commercial3,5-bis(trifluoromethyl)acetophenone (2.1 g) was added. After 12 hr themixture was cooled at 0° C. and then NaBH₄ (0.512 g) was added. After 1hr the mixture was quenched with H₂O and extracted with DCM. Then theorganic phase was dried and concentrated to give the crude product whichwas purified by distillation to obtain the title compound (1.5 g) as anoil.

NMR (CDCl₃) δ (ppm) 7.8 (m, 3H); 3.8 (q, 1H); 2.4 (s, 3H); 1.4 (d, 3H)

Intermediate 224-{[1-(3,5-Bis-trifluoromethyl-phenyl)-ethyl]-methyl-carbamoyl}-3-(4-fluoro-2-methyl-phenyl)-piperazine-1-carboxylicacid benzyl ester (mixture of enantiomers A,B) (22a)4-{[1-(3,5-Bis-trifluoromethyl-phenyl)-ethyl]-methyl-carbamoyl}-3-(4-fluoro-2-methyl-phenyl)-piperazine-1-carboxylicacid benzyl ester (mixture of enantiomers C,D)(22b)

To a solution of4-benzyloxycarbonyl-2-(4-fluoro-2-methyl-phenyl)-piperazine-1-carbonylchloride (0.075 g) in DCM (5 mL) DIPEA (0.12 mL) and intermediate 21(0.1 g) were added. The mixture was refluxed for 2 hr, then acetonitrile(5 mL) was added and the obtained solution was heated 70° C. and themixture was stirred overnight. Then the mixture was concentrated and theresidue was dissolved in AcOEt. The organic phase was washed with HCl 1Nand brine and dried. The organic phase was concentrated to give thecrude mixture of diastereomeric compounds which were separated by flashchromatography (CH/AcOEt 8:2) to obtain the title compound 22a (0.05 g)and title compound 22b (0.55 g) as white foams.

Intermediate 22a: NMR (CDCl₃) δ (ppm) 7.78 (s, 1H); 7.58 (s, 2H);7.4-7.3 (m, 5H); 7.18 (m, 1H); 6.86 (m, 1H); 6.77 (m, 1H); 5.45 (m, 1H);5.16 (s, 2H); 4.6 (m, 1H); 3.94 (m, 2H); 3.44-3.10 (m, 4H); 2.68 (s,3H); 2.4 (s, 3H); 1.49 (d, 3H).

Intermediate 22b: NMR (CDCl₃) δ (ppm) 7.75 (s, 1H); 7.53 (s, 2H);7.4-7.3 (m, 5H); 7.18 (m, 1H); 6.87 (m, 1H); 6.78 (m, 1H); 5.59 (m, 1H);5.18 (s, 2H); 4.59 (m, 1H); 3.97 (m, 2H); 3.44-3.06 (m, 4H); 2.78 (s,3H); 2.37 (s, 3H); 1.53 (d, 3H).

Intermediate 23 (4-Fluoro-2-methyl-phenyl)-oxo-acetic acid methyl ester

1) To a suspension of magnesium turnings (617 mg) in anh. THF (6 mL), atr.t., under N₂, a small crystal of I₂ was added, followed by 10% of asolution of commercial 2-bromo-5-fluorotoluene (4.0 g) in anh. THF (15mL). The suspension was heated gently (heat gun) until the brown colourdisappeared. The remaining bromide solution was added drop-wise,maintaining the reaction mixture warm (50-60° C.) with an oil bath.After the addition was complete (15 min), the suspension was stirred at70° C. until the magnesium turnings had almost completely reacted (2hr). The new brown solution was used in the next step.

2) A solution of LiBr (4.41 g) in anh. THF (50 mL) was added drop-wiseto a suspension of CuBr (3.64 g) in anh. THF (50 mL). The reactionmixture was stirred at r.t. for 1 hr (dark green solution with a smallamount of white solid in suspension). The Grignard solution previouslyprepared was then added dropwise (an ice bath was used to maintain thetemperature <25° C.) followed by methyl oxalyl chloride (1.95 mL). Thereaction mixture was stirred at r.t. for 2 hr. The THF was evaporatedand the residue was taken up in AcOEt. The organic layer was washed withsat.aq. NH₄Cl (2×) and dried. The solids were filtered and the solventevaporated to give a crude oil, which was purified by flashchromatography (CH/AcOEt 95:5) to obtain the title compound as a clearoil (2.44 g).

NMR (CDCl₃): δ (ppm) 7.74 (m, 1H), 6.98-7.04 (m, 2H), 3.96 (s, 3H), 2.61(s, 3H).

Intermediate 24 (4-Fluoro phenyl)-oxo-acetic acid methyl ester

To magnesium turnings (0.066 g), previously heated at 90° C. and coveredby THF (1 mL), a crystal of iodine was added followed by a solution ofcommercial 4-Fluoro-bromobenzene (0.437 g) in THF (4 mL). Thetemperature was kept at 60° C. till the consumption of the metal. Thesolution of the organometallic derivative was added drop-wise on asolution of CuBr (0.356 g) and LiBr (0.431 g) in THF (10 mL), previouslyprepared at 0° C.

At the end of the addition, methyl oxalyl chloride (0.225 mL) was addedvia syringe and the reaction mixture was stirred 2 h at r.t, beforebeing poured into an aqueous saturated solution of NH₄Cl and extractedwith Et₂O. The organic phase was washed with brine and dried. The crudeproduct obtained after evaporation of solvents was purified by columnchromatography (CH/AcOEt 95:5) affording the title compound (0.2 g) as asolid.

¹H-NMR (CDCl₃): δ (ppm): 8.12 (m, 2H), 7.20 (m, 2H), 3.99 (s, 3H).

Intermediate 253-(4-Fluoro-2-methyl-phenyl)-5,6-dihydro-1H-pyrazin-2-one

To a solution of intermediate 23 (2.01 g) and ethylenediamine (684 μL)in toluene (40 mL), at r.t., under N₂, anh. Na₂SO₄ (2 g) was added. Thereaction mixture was heated at reflux for 6 hr. It was then cooled downto r.t. and filtered. The solids were rinsed with DCM. The solvent wasevaporated and the crude oil was purified by flash chromatography(AcOEt) affording the title compound as a white solid (1.29 g).

NMR (CDCl₃): δ (ppm) 7.33 (m, 1H), 6.95-6.90 (m, 2H), 6.56 (m, 1H), 3.97(m, 2H), 3.58 (m, 2H), 2.31 (s, 3H).

Intermediate 25a 3-(4-Fluoro-2-methyl-phenyl)-piperazin-2-one

To a solution, at 25° C., of intermediate 25 (168 g) in Methanol (2400mL) under nitrogen, Pd/C 10% (44 g) was added. The reaction mixture wasplaced under a H₂ atmosphere and stirred at 25° C. for about 16 hours(till no further hydrogen was consumed and the reaction was completed byTLC, EA/MeOH 9/1). The catalyst was filtered in nitrogen atmosphere andthe solvent was removed to low volume (360 mL) then Methanol (2040 mL)and Ethyl Acetate (9600 mL) were added and a silica pad (800 g) wasperformed; the eluted solution was concentrated to obtain the titlecompound (168 g).

¹H-NMR (DMSO) δ (ppm) 7.77 (bm, 1H); 7.24 (dd, 1H); 6.96 (dd, 1H); 6.92(td, 1H); 4.43 (s, 1H); 3.30 (m, 1H); 3.14 (m, 1H); 2.92 (m, 1H); 2.82(m, 2H); 2.33 (s, 3H).

Intermediate 26 3-(4-Fluoro-phenyl)-5,6 dihydro-1H-pyrazin-2-one

Intermediate 24 (0.190 g) was dissolved in dry toluene (5 mL) underinert atmosphere; ethylenediamine (0.072 mL) was added dropwise followedby Na₂SO₄ (0.2 g) and the reaction mixture was refluxed 2 hr. The solidswere filtered off and the crude product obtained after evaporation ofthe solvent was purified by flash chromatography (AcOEt/MeOH 9:1)affording the title compound (0.155 g as a white solid).

mp 118-120° C.

¹H-NMR (CDCl₃) δ (ppm): 7.96 (m, 2H), 7.08 (m, 2H), (bs, 1H), 3.96 (t,2H), 3.54 (m, 2H).

Intermediate 27 Bromo-(2,4-dichloro-phenyl)-acetic acid methyl ester

To a stirred solution of commercial 2,4-dichlorophenylacetic acid (2 g)in DCM (50 mL) DMF (0.1 mL) and oxalyl chloride (1.7 mL) were added andthe reaction mixture was heated at reflux for 1½ hr. The solvent wasevaporated and the crude compound was dissolved in carbon tetrachloride(40 mL). N-bromosuccinimide (1.8 g) and2,2′-azobis(2-methylpropionitrile) (0.1 g) were added and the reactionmixture was heated at reflux and irradiated for 2 hr. After cooling,methanol (50 mL) was added and the reaction mixture was stirred for 1hr. The solution was concentrated, diluted with AcOEt and washed with a3N HCl and brine. The organic phase was dried and concentrated to give acrude residue, which was purified by flash chromatography (CH/AcOEt 9:1)to obtain a mixture of the title compound and 2,4-dichlorophenyl-aceticacid methyl ester (1.3 g).

This mixture was dissolved in carbon tetrachloride (20 mL) thenN-bromosuccinimide (0.89 g) and 2,2′-azobis(2-methylpropionitrile) (0.05g) were added and the reaction mixture was heated at reflux andirradiated for 3½ hr. The solution was concentrated, diluted with AcOEtand washed with a saturated solution of Na₂CO₃ and brine. The organicphase was dried and concentrated to give a crude residue which waspurified by flash column chromatography (CH/AcOEt 9:1) to yield thetitle compound (1.14 g, pale yellow oil).

NMR (CDCl₃): δ (ppm) 7.72 (d, 1H), 7.40 (d, 1H), 7.30 (dd, 1H), 5.84 (s,1H), 3.81 (s, 3H)

Intermediate 28 Bromo-(3,4-dichloro-phenyl)-acetic acid methyl ester

DMF (0.1 ml) and oxalyl chloride (1.7 ml) were added to a solution ofcommercial 3,4-dichlorophenylacetic acid (2 g) in DCM (100 ml) and thereaction mixture was heated at reflux for 1½ hr. After cooling, methanol(50 mL) was added and the reaction mixture was stirred for 1 hr. Thesolvent was evaporated and the crude compound was purified by flashchromatography (CH/AcOEt 9:1) to obtain the methyl ester that wasdissolved in carbon tetrachloride (60 mL). N-Bromosuccinimide (2.06 g)and 2,2′-azobis(2-methylpropionitrile) (0.2 g) were added and thereaction mixture was heated at reflux and irradiated for 2 hr. Thesolution was concentrated, diluted with ethyl acetate and washed with asaturated solution of Na₂CO₃ and brine. The organic phase was next driedwith Na₂SO₄ and concentrated to give a crude residue which was purifiedby flash chromatography (CH/AcOEt 9:1) to obtain the title compound (2.0g) as an oil.

NMR (CDCl₃) δ (ppm) 7.70 (s, 1H), 7.45 (m, 1H), 5.25 (s, 1H), 3.80 (s,3H)

Intermediate 29 3-(2,4-Dichloro-phenyl)-piperazine-2-one

To a solution of intermediate 27 (1.14 g) in EtOH (20 mL) sodiumethoxide (0.34 g) and ethylenediamine (0.54 mL) were added and thereaction mixture was stirred at r.t. for 15 hr. The solvent wasevaporated and the residue was purified by flash chromatography to yieldthe title compound (0.35 g) as a white foam.

NMR (DMSO): δ (ppm) 7.87 (broad, 1H), 7.55 (d, 1H), 7.41, 7.37 (d+dd,2H), 4.63 (s, 1H), 3.32, 3.14 (m+m, 2H), 3.02-2.90, 2.84 (m+m, 3H).

Intermediate 30 3-(3,4-Dichloro-phenyl)-piperazine-2-one

To a solution of intermediate 28 (2.0 g) in EtOH (100 ml) sodiumethoxide (0.60 g) and ethylenediamine (0.95 ml) were added and thereaction mixture was stirred at r.t. for 15 hr. The solvent wasevaporated and the residue was diluted with ethyl acetate and washedwith brine. The organic phase was dried and concentrated to give thetitle compound (2.0 g) as a white foam).

NMR (CDCl₃): δ (ppm) 7.60 (d, 1H), 7.42 (d, 1H), 7.32, (dd, 1H), 5.91(sa, 1H), 4.53 (s, 1H), 3.6-3.1 (m+m, 4H).

Intermediate 31 3-Oxo-2-phenyl-piperazine-1-carbonyl chloride

To a stirred solution of triphosgene (0.558 g) in DCM (10 ml) pyridine(0.46 mL) was added at 0° C. and, after 10 min,3-phenyl-piperazine-2-one (1 g). The ice bath was removed and themixture was stirred at room temperature overnight. The mixture wasconcentrated and the product was purified by flash chromatography(CH/AcOEt 1:1) to give the title compound (0.253 g) as a foam.

NMR (CDCl₃): δ (ppm): 7.45-7.35 (m, 5H); 6.81 (bs, 1H); 6.61 (bs, 1H);5.99 (s, 1H); 4.3-4.2 (m, 1H); 3.7-3.3 (m, 3H)

Intermediate 322-(4-Fluoro-2-methyl-phenyl)-3-oxo-piperazine-1-carboxylic acid(3,5-bis-trifluoromethyl-benzyl)-methyl-amide

To a solution of intermediate 25 (63 mg) in anh. MeOH (6.1 mL), at r.t.,under N₂, Pd/C 10% (7 mg, 10% wt) was added. The reaction mixture wasplaced under an H₂ atmosphere and was stirred at r.t. for 2 hr. Thecatalyst was filtered (filtering paper) and the solvent was evaporated.The crude 3-(4-Fluoro-2-methyl-phenyl)-piperazin-2-one (64 mg) was driedunder high vacuum and dissolved in anh. DCM (4.0 mL), at 0° C., underN₂, and TEA (85 μL) was added. Then, a solution of triphosgene (37 mg)in anh. DCM (2 mL) was added drop-wise. The reaction was stirred at 0°C. for 2 hr. To this solution DIPEA (107 μL) andN-methyl-bis(trifluoromethyl)-benzylamine hydrochloride (108 mg) wereadded. The solution was stirred at r.t. for 18 hr. The reaction mixturewas diluted with DCM, washed with 1N HCl (1×) and dried. The solids werefiltered and the solvent evaporated. The crude product was purified byflash chromatography (AcOEt) to give the title compound as a white solid(93 mg).

NMR (CDCl₃): δ (ppm) 7.79 (s, 1H), 7.59 (s, 2H), 7.20 (bs, 1H),6.91-6.84 (m, 1H), 6.07 (m, 1H), 5.69 (s, 1H), 4.58-4.47 (dd, 1H), 3.49(m, 4H), 2.85-2.39 (s, 6H).

Intermediate 33 2-(4-Fluoro-phenyl)-3-oxo-piperazine-1-carboxylic acid(3,4-bis-trifluoromethyl-benzyl)-methyl-amide

Intermediate 26 (0.135 g) was dissolved in MeOH (5 mL) and thetemperature lowered at 0° C., then NaBH₄ (0.102 g) was carefully added.After 2 hr the reduction was complete, the solvent was removed underreduced pressure and DCM was added. The organic phase was washed withH₂O and brine before being dried on Na₂SO₄. The crude3-(4-Fluoro-phenyl)-piperazin-2-one (0.140 g) was dried under highvacuum and dissolved in anhydrous DCM (5 mL), at 0° C. and TEA (0.433mL) was added drop-wise. To this solution a solution of triphosgene(0.09 g) in dry DCM (3 mL) was added at 0° C., under inert atmosphere.The temperature was maintained at 0° C. for 3 hr, then DIPEA (0.4 mL)followed by 3,5-bistrifluoromethyl-methyl-amine hydrochloride (0.27 g)were added. The reaction mixture was stirred at r.t. overnight beforebeing diluted with DCM and washed with a 1N solution of HCl, H₂O andbrine. The organic phase was dried and the crude product obtained afterevaporation of the solvent was purified by flash column chromatography(AcOEt) affording the title compound as a foam (0.2 g).

NMR (DMSO): δ (ppm) 8.14 (bs, 1H), 7.97 (s, 1H), 7.78 (s, 2H), 7.37 (m,2H), 7.09 (m, 2H), 5.13 (s, 1H), 4.49 (dd, 2H), 3.5-3.25 (m, 4H), 2.80(s, 3H).

Intermediate 34 3-Oxo-2-phenyl-piperazine-1-carboxylic acid(3,5-bis-trifluoromethyl-benzyl)-methyl-amide

To a stirred solution of intermediate 31 (0.239 g) in DMF (5 mL) DIPEA(0.41 mL) and 3,5-bistrifluoromethyl-methyl-amine hydrochloride (0.366g) were added. After 3 hr the mixture was quenched with brine and theaqueous layer was extracted with AcOEt. The organic layer was dried andconcentrated at reduced pressure. The product was purified by flashchromatography (AcOEt) to give the title compound (0.429 g).

NMR (CDCl₃): δ (ppm): 7.79 (bs, 1H); 7.67 (bs, 2H); 7.50 (d, 2H); 7.35(m, 3H); 5.98 (s, 1H); 5.43 (s, 1H): 4.63-4.32 (dd, 2H); 3.88-3.56 (m,2H); 3.50-3.30 (m, 2H); 2.81 (s, 3H).

Intermediate 35 2-(2,4-Dichloro-phenyl)-3-oxo-piperazine-1-carboxylicacid (3,5-bis-trifluoromethyl-benzyl)-methyl-amide

To a solution of intermediate 29 (0.33 g) in DCM (30 mL) TEA (0.65 mL)and, dropwise, a solution of triphosgene (0.23 g) in DCM (10 mL) wereadded. The reaction mixture was stirred at r.t. for 1½ hr thenconcentrated and purified by flash chromatography to yield2-(2,4-dichloro-phenyl)-3-oxo-piperazine-1-carbonyl chloride (0.3 g,white foam). The latter was dissolved in DCM (30 mL), then DIPEA (0.3mL) and (3,5-bistrifluoromethylbenzyl)-methyl-amine hydrochloride (0.32g) were added. The reaction mixture was stirred at reflux for 3 hr, thenwashed with a 1N solution of HCl and brine. The organic phase was nextdried and concentrated to give the crude product which was purified byflash chromatography (from AcOEt 100% to AcOEt/MeOH 8:2) to obtain thetitle compound (0.45 g) as a white foam.

NMR (DMSO) δ (ppm) 8.30 (bs, 1H), 7.96 (bs, 1H), 7.73 (bs, 1H), 7.54 (d,1H), 7.35, 7.33 (d+dd, 2H), 5.44 (s, 1H), 4.61 (d, 1H), 4.39 (d, 1H),3.39, 3.25 (m+m, 4H), 2.76 (s, 3H).

Intermediate 36 2-(3,4-Dichloro-phenyl)-3-oxo-piperazine-1-carboxylicacid (3,5-bis-trifluoromethyl-benzyl)-methyl-amide

To a solution intermediate 30 (0.413 g) in DCM (40 mL) TEA (1.4 mL) and,dropwise, a solution of triphosgene (0.25 g) in DCM (10 mL) was added.The reaction mixture was stirred at r.t. for 1½ hr, then DIPEA (0.6 mL)and (3,5-bistrifluoromethylbenzyl)-methyl-amine hydrochloride (0.54 g)were added. The reaction mixture was stirred at reflux for 3 hr, thenwashed with a 1N solution of HCl and brine. The organic phase was nextdried and concentrated to give the crude product which was purified byflash chromatography (from AcOEt 100% to AcOEt/MeOH 8:2) to give thetitle compound (0.13 g, white foam).

NMR (DMSO) δ (ppm) 8.24 (bs, 1H), 7.96 (s, 1H), 7.75 (s, 2H), 7.54 (d,1H), 7.51 (d, 1H), 7.33 (dd, 1H), 5.11 (s, 1H), 4.49 (dd, 2H), 3.5-3.25(m+m, 4H), 2.82 (s, 3H).

Intermediate 374-(3,5-Bis-trifluoromethyl-benzyl-carbamoyl)-3-(4-fluoro-2-methyl-phenyl)-piperazine-1-carboxylicacid 1-(R)-phenyl-ethyl ester (diastereomer 1) (37a)4-(3,5-Bis-trifluoromethyl-benzyl-carbamoyl)-3-(4-fluoro-2-methyl-phenyl)-piperazine-1-carboxylicacid 1-(R)-phenyl-ethyl ester (diastereomer 2) (37b)

To a solution of carbonyl diimidazole (402 mg) in DCM (8.3 mL), at r.t.,under N₂, (R)-sec-phenylethyl alcohol (0.3 mL) was added. The solutionwas stirred at r.t. for 1 hr. Example 11 (790 mg) in anh. acetonitrile(8.3 mL) was then added to the solution and the reaction mixture washeated at 50° C. without a water condenser in order to evaporate theDCM. A water condenser was then adjusted to the flask and the reactionmixture was refluxed for 4 hr. The solvent was then evaporated and theresidue partitioned between AcOEt/1N HCl. The phases were separated andthe organic layer was washed with sat. aq. NaCl (2×). It was then driedand the solvent evaporated. The crude oil was purified by flashchromatography (CH/AcOEt 8:2). The mixed fractions werere-chromatographed using the same conditions. Intermediates 37a (242 mg)and 37b (152 mg) were obtained as white foams.

Intermediate 37a: NMR (DMSO) δ (ppm): 7.90 (s, 1H); 7.67 (s, 2H);7.37-7.24 (m, 6H); 6.95 (dd, 1H); 6.81 (m, 1H); 5.75 (q, 1H); 4.60-4.41(dd, 2H); 4.52 (m, 1H); 3.83-3.00 (m, 6H); 2.88 (s, 3H); 2.33 (s, 3H);1.48 (d, 3H).

Intermediate 37b: NMR (DMSO) δ (ppm): 7.90 (s, 1H); 7.67 (s, 2H);7.4-7.27 (m, 6H); 6.95 (dd, 1H); 6.80 (m, 1H); 5.74 (q, 1H); 4.60-4.40(dd, 2H); 4.50 (m, 1H); 3.79 (m, 3H); 3.00 (m, 3H); 2.87 (s, 3H); 2.29(s, 3H); 1.46 (d, 3H).

Intermediate 384-{[1-(S)-(3,5-Bis-trifluoromethyl-phenyl)-ethyl]-methyl-carbamoyl}-3-(S)-(4-fluoro-2-methyl-phenyl)-piperazine-1-carboxylicacid 1-(R)-phenyl-ethyl ester (diastereomer 1) (38a)4-{[1-(R)-(3,5-Bis-trifluoromethyl-phenyl)-ethyl]-methyl-carbamoyl}-3-(R)-(4-fluoro-2-methyl-phenyl)-piperazine-1-carboxylicacid 1-(R)-phenyl-ethyl ester (diastereomer 2) (38b)

To a solution of 1,1′Carbonyldiimidazole (0.163 g) in DCM (5 mL)(R)-sec-phenethyl alcohol (0.122 g) was added and the mixture wasstirred at room temperature for 30 min. Then a solution of example 10(0.250 g) in acetonitrile (5 mL) was added and the mixture was refluxedfor 4 hr. The mixture was cooled and AcOEt was added. The organic phasewas washed with HCl 1N (2×50 mL) and brine, dried and concentrated togive the crude mixture of diastereomers, which were separated by flashchromatography (CH/AcOEt 8:2) to obtain the title compound 38a(diastereomer 1-0.08 g) and the title compound 38b (diastereomer 2-0.08g).

Intermediate 38a: NMR (CDCl₃) δ (ppm) 7.74 (s, 1H); 7.52 (s, 2H);7.40-7.24 (m, 5H); 7.18 (m, 1H); 6.87 (m, 1H); 6.80 (m, 1H); 5.86 (q,1H); 5.57 (q, 1H); 4.7-4.46 (m, 1H); 3.98 (m, 2H); 3.44-2.96 (m, 4H);2.77 (s, 3H); 2.36 (s, 3H); 1.54 (m, 6H).

Intermediate 38b NMR (CDCl₃) δ (ppm) 7.74 (s, 1H); 7.53 (s, 2H);7.40-7.26 (m, 5H); 7.16 (m, 1H); 6.87 (m, 1H); 6.78 (m, 1H); 5.86 (q,1H); 5.57 (m, 1H); 4.62 (m, 1H); 4.04 (m, 1H); 3.84 (m, 1H): 3.50-3.04(m, 4H); 2.76 (s, 3H); 2.41 (s, 3H); 1.56 (m, 6H).

Intermediate 39 (+)(S)-3-(4-Fluoro-2-methyl-phenyl)-piperazin-2-oneMethod A

To a suspension of intermediate 25 (35 g) in AcOEt (900 mL),L(+)-Mandelic Acid (27.3 g) was added. The suspension was stirred atr.t. for 1 hr then at 3-5° C. for 2 hr, filtered and dried under vacuumat r.t to obtain crude L(+)-mandelate3-(4-fluoro-2-methyl-phenyl)-piperazin-2-one (37 g), which was suspendedin AcOEt (370 mL) and heated to reflux till complete solubilisation thencooled to room temperature and stirred for further 2 hours, filtered,washed with of AcOEt (150 mL) and dried under vacuum obtaining (+)L-mandelate 3-(4-Fluoro-2-methyl-phenyl)-5,6 pyrazin-2-one (30.4 g) aswhite solid. This material (30.4 g) was suspended in AcOEt (300 mL) andtreated with NaOH (0.73M, 155 mL) saturated with NaCl. The organic phasewas then washed with water (90 mL). The aqueous phase wascounter-extracted 4 times with AcOEt (90 mL). The combined organic phase(1800 mL) was dried on 10 g of Na₂SO₄ and concentrated under vacuumobtaining the title compound (25.04 g) as white foam.

Method B

To a solution, heated at 45° C., of intermediate 25a (168 g) in EthylAcetate (2000 mL) L(+)-Mandelic Acid (116 g) and3,5-dichloro-salicilaldehyde (10.8 g) were added. The solution wasstirred for 30 min at 45° C. then seeded with white crystals ofL(+)mandelate-3-(4-Fluoro-2-methyl-phenyl)-piperazin-2-one (0.4 g). Theobtained suspension was stirred under nitrogen atmosphere at 45° C. for16 hours then stirred for further 4 hour at 0° C., washed with cooledEthyl Acetate (2×200 ml) then dried under vacuum at room temperature for2 hours to obtainL(+)mandelate-3-(4-Fluoro-2-methyl-phenyl)-piperazin-2-one (126.22 g) asa white/yellowish solid which was suspended in DCM (2760 mL) then NaOH0.8M in Brine (17.35 g of NaOH in 530 mL of Brine) was added. Theorganic phase was then washed with Brine (380 mL) and the aqueous phasewas counter extracted four times with DCM (4×1500 mL). The combinedorganic phase was dried and concentrated to obtain the title compound(60.35 g).

¹H-NMR (DMSO) δ (ppm) 7.77 (bm, 1H); 7.24 (dd, 1H); 6.96 (dd, 1H); 6.92(td, 1H); 4.43 (s, 1H); 3.30 (m, 1H); 3.14 (m, 1H); 2.92 (m, 1H); 2.82(m, 2H); 2.33 (s, 3H).

HPLC: Chiralcel OJ (4.6×250 mm) from Daicel; MobilePhase:n-Hexane/Ethanol 80:20 v/v; Flow: 1 mL/min; Detector: UV @ 265 nm(or 210 nm for higher signals); Dissolution phase: n-Hexane/Ethanol80/20 v/v; Sample Concentration 1 mg/ml; Injection: 5 uL; Retentiontimes: 2:8.4 min. [α]_(D) (solvent CHCl₃, Source: Na; Cell volume [ml]:1; Cell pathlength [dm]: 1; Cell temperature [° C.]: 20; Wavelength[nm]: 589; Conc. sample [% p/v]: 1.17)=+17.9.

Intermediate 402-(S)-(4-Fluoro-2-methyl-phenyl)-3-oxo-piperazine-1-carboxylic acid[1-(R)-(3,5-bis-trifluoromethyl-phenyl)-ethyl]-methyl-amide (40a)2-(S)-(4-Fluoro-2-methyl-phenyl)-3-oxo-piperazine-1-carboxylic acid[1-(S)-(3,5-bis-trifluoromethyl-phenyl)-ethyl]-methyl-amide (40b)

To a solution of intermediate 39 (12.1 g) in anhydrous DCM (270 mL), TEA(16.4 mL) was added. The solution was cooled down to 0° C. and asolution of triphosgene (7.3 g) in anh. DCM (60 mL) was added drop-wiseover 40 min. The reaction mixture was stirred at 0° C. for 4 hr and wasbrought back to r.t. DIPEA (20.2 mL) was then added, followed by asolution of [1-(3,5-bis-trifluoromethyl-phenyl)-ethyl]-methyl-amine(23.6 g) in acetonitrile (300 mL) and an additional amount ofacetonitrile (300 mL). The reaction mixture was warmed up to 95° C. (oilbath T° C.) without a water condenser to evaporate the DCM. When theinternal temperature had reached 70° C., the flask was equipped with awater condenser, and the reaction mixture was heated at 70° C. for anadditional 2 hr (4 hr total). It was then brought back to r.t. and thesolvent was evaporated. The residue was partitioned between DCM/2% HCland the phases were separated. The aqueous layer was extracted with DCM(1×) and the combined organic extracts were dried. The solids werefiltered and the solvent evaporated to give a crude mixture of titlecompounds which were purified by flash chromatography (AcOEt/CH 8:2) toobtain the title compounds 40a (8.8 g) and 40 b (9.0 g) as white foams.

NMR (1H, DMSO-d₆): δ 8.16 (s, 1H), 7.98 (s, 2H), 7.19 (dd, 1H), 6.97(dd, 1H), 6.87 (td, 1H), 5.34 (s, 1H), 5.14 (q, 1H), 3.45-3.2 (m, 4H),2.53 (s, 3H), 2.27 (s, 3H), 1.56 (d, 3H).

Intermediate 40b: NMR (1H, DMSO-d₆): δ 8.16 (s, 1H), 7.95 (s, 2H), 7.19(dd, 1H), 6.98 (dd, 1H), 6.90 (td, 1H), 5.29 (q, 1H), 5.28 (s, 1H),3.45-3.15 (m, 4H), 2.66 (s, 3H), 2.27 (s, 3H), 1.52 (d, 3H).

Intermediate 414-[2-(1,3-Dioxo-1,3-dihydro-isoindol-2-yl)-ethyl]-2-(4-fluoro-2-methyl-phenyl)-piperazine-1-carboxylicacid (3,5-bis-trifluoromethyl-benzyl)-methyl-amide

To a solution of example 8 (0.05 g) in anhydrous DMF (1 mL), under N₂,at room temperature, were added TEA (40 μl) andN-(2-bromoethyl)-phthalimide (28 mg). The reaction mixture was stirredat 80° C. for 5 hr and was then cooled down to room temperature. It waspoured in sat.aq. NaCl and the phases were separated. The organic layerwas washed with sat. aq. NaCl (2×), dried and the solvent evaporated.The crude product was purified by flash chromatography (CH/AcOEt 1:1) togive the title compound (0.25 g) as a yellow oil.

NMR (DMSO) δ (ppm) 7.94 (s, 1H), 7.80-7.90 (m, 4H), 7.67 (s, 2H), 7.33(m, 1H), 6.91 (dd, 1H), 6.45 (td, 1H), 4.60 (d, 1H), 4.34 (m, 2H), 3.80(m, 1H), 3.64 (m, 1H), 3.18 (m, 1H), 2.82 (s, 3H), 2.79 (m, 1H), 2.80(m, 1H), 2.66 (m, 1H), 2.60 (m, 2H), 2.46 (m, 1H), 2.26 (m, 1H), 2.27(s, 3H).

IR (Nujol) (cm⁻¹) 1650-1773.

MS (m/z) 651 [MH], 673 [M+Na]⁺.

Intermediate 42 1-(4-Fluoro-2-methyl-phenyl)-propane-1,2-dione

1) To a suspension of magnesium turnings (283 mg) in anh. THF (3 mL), atr.t., under N₂, was added a small crystal of 12, followed by 10% of asolution of 1-bromo-4-fluoro-2-methyl-benzene (2.0 g) in anhydrous. THF(8 mL). The suspension was heated gently (heat gun) until the browncolour disappeared. The remaining bromide was added drop-wise,maintaining the reaction mixture warm (50-60° C.) with an oil bath.After the addition was complete (15 min) the suspension was stirred at70° C. until the magnesium turnings had almost completely reacted (2hr). The new brown solution was used in the next step.

2) A solution of LiBr (2.26 g) in anh. THF (26 mL) was added drop-wise asuspension of CuBr (1.82 g) in anh. THF (26 mL). The reaction mixturewas stirred at r.t. for 1 hr. The reaction mixture was then brought at−78° C. and the Grignard solution prepared above was added dropwisefollowed by pyruvyl chloride (1.13 g). The reaction mixture was stirredat −78° C. for 2 hr. The THF was evaporated and the residue was taken upin AcOEt. The organic layer was washed with sat.aq. NH₄Cl (2×), driedand evaporated to a crude oil, which was purified by flashchromatography (CH/AcOEt 95:5) to give the title compound as a yellowoil (0.58 g).

NMR (CDCl₃) δ (ppm). 7.68 (m, 1H), 6.98 (m, 2H), 2.56-2.52 (2s, 6H).

IR (Film) (cm⁻¹) 1712, 1674.

Intermediate 435-(4-Fluoro-2-methyl-phenyl)-6-methyl-2,3-dihydro-pyrazine

To a solution of intermediate 42 (0.58 g) and ethylenediamine (0.22 mL)in toluene (13 mL), at r.t., under N₂, was added anh. Na₂SO₄ (2 g). Thereaction mixture was heated at reflux for 6 hr. It was then cooled downto r.t. and filtered. The solids were rinsed with DCM. The solvent wasevaporated and the crude oil was purified by flash chromatography(AcOEt) to give the title compound as an orange oil (0.44 g).

NMR (CDCl₃) δ (ppm) 7.18 (m, 1H), 7.0-6.9 (m, 2H), 3.6-3.45 (2m, 4H),2.20 (s, 3H), 1.88 (t, 3H).

IR (Film) (cm⁻¹) 1612, 1530.

MS (m/z) 204 [M]⁺.

Intermediate 442-Methyl-3-(2-methyl-4-fluoro)-phenyl-piperazine-1-carboxylic acidbenzyl ester

To a solution of intermediate 43 (554 mg) in anh. MeOH (11 mL), underN₂, at r.t., was added Pd/C 10% (110 mg) and the reaction mixture wasplaced under an H₂ atmosphere for 2 hr. The catalyst was then filtered(filter paper) and rinsed with AcOEt. The solvent was evaporated and theresidue dried under vacuum. 2-(4-Fluoro-2-methyl-phenyl)-3-methylpiperazine was obtained as a yellow oil (565 mg) and was dissolved inanh. DCM (27 mL), at −5° C., under N₂. TEA (549 μL) andbenzyloxycarbonyl chloride (426 μL) were added to this solution. Thesolution was stirred at −5° C. for 2 hr., then it was poured in sat.aq.NaHCO₃/DCM and the phases were separated. The aqueous layer wasextracted with DCM (1×) and the combined organic extracts were dried.The solids were filtered and the solvent evaporated. The crude oil waspurified by flash chromatography (CH/AcOEt 1:1) to give the titlecompound was obtained as a yellow oil (111 mg).

NMR (CDCl₃) δ (ppm) 7.45-7.36 (m, 6H), 6.86 (m, 2H), 5.17 (m, 2H),4.48-4.36 (m, 1H), 4.09-4.04 (2d, 1H), 4.05-3.94 (2bd, 1H), 3.25-2.88(m, 3H), 2.40+2.28 (2s, 3H), 0.97+0.96 (2d, 3H).

IR (Film) (cm⁻¹) 1688.

MS (m/z) 343 [MH]⁺.

Intermediate 454-[(3,5-Bis-trifluoromethyl-benzyl)-methyl-carbamoyl]-3-(4-fluoro-2-methyl-phenyl)-2-methyl-piperazine-1-carboxylicacid benzyl ester

To a solution of intermediate 44 (358 mg) in anh. DCM (15 mL), at 0° C.,under N₂, was added TEA (292 μL). To this solution was added a solutionof triphosgene (140 mg) in anh. DCM (6 mL). The reaction mixture wasstirred at 0° C. for 2 hr.

To this solution were added DIPEA (181 μL) andN-methyl-bis(trifluoromethyl)benzylamine hydrochloride (370 mg). Thesolution was stirred at r.t. for 18 hr. It was then diluted with DCM,washed with 10% citric acid (1×) and dried. The solvent was evaporatedand the crude oil purified by flash chromatography (CH/AcOEt 6:4) togive the title compound (545 mg) as a white foam.

NMR (CDCl₃) δ (ppm) 7.76 (s, 1H), 7.50 (s, 2H), 7.34-7.30 (m, 5H), 7.00(m, 1H), 6.85 (m, 1H), 6.76 (m, 1H), 5.2-5.1 (dd, 2H), 4.75 (d, 1H),4.30 (d, 1H), 4.65 (m, 1H), 4.35 (m, 1H), 4.00 (m, 1H), 3.54-3.40 (m,2H), 3.1 (m, 1H), 3.06 (s, 3H), 2.38 (s, 3H), 1.05 (d, 3H).

IR (Film) (cm⁻¹) 3437, 1705, 1664.

MS (m/z) 626 [MH]⁺.

Intermediate 463-(2-Methyl-4-fluoro-phenyl)-5-methyl-5,6-dihydro-1H-pyrazin-2-one

Under inert atmosphere, intermediate 23 (0.2 g) was dissolved in drytoluene (5 mL), then 1,2-diaminopropane (0.102 mL) was added drop-wisefollowed by Na₂SO₄ (0.2 g) and the reaction mixture was refluxed for 2hr; the solids were filtered off and the crude product obtained afterevaporation of the solvent was purified by flash chromatography (AcOEt)affording the title compound in a mixture with3-(2-Methyl-4-fluoro-phenyl)-6-methyl-5,6-dihydro-1H-pyrazin-2-one(0.200 g).

¹H-NMR (DMSO) δ (ppm) 8.42 (bs, 1H), 7.24 (m, 1H), 7.02 (m, 2H), 3.85(m, 1H), 3.40 (dt, 1H), 3.13 (t, 1H), 2.18 (s, 3H), 1.25 (d, 3H).

IR (Nujol) (cm⁻¹) 3450, 1682, 1614. MS (m/z) 221 [MH]⁺.

Intermediate 47 3-(2-Methyl-4-fluoro-phenyl)-5-Methyl-piperazin-2-one(mixture of syn enantiomers)

Intermediate 46 (0.180 g) was dissolved in MeOH (4 mL) and Pd/C 10% (36mg) was added. After 2 hr the reduction was complete. The reactionmixture was filtered on a celite pad, the solvent was removed underreduced pressure and the crude product purified by flash-chromatography(AcOEt/MeOH 9:1) affording a 9:1 mixture of the title compound and theanti enantiomers (0.110 g).

¹H-NMR (DMSO) δ (ppm) 7.88 (s, 1H), 7.07-6.92 (m, 3H), 4.48 (s, 1H), 3.3(m, 1H), 2.91 (m, 2H), 2.65 (bs, 1H), 2.34 (s, 3H), 0.95 (d, 3H).

IR (Nujol) (cm⁻¹) 3441, 3285, 1675.

MS (m/z): 223 [MH]⁺.

Intermediate 482-(2-Methyl-4-fluoro-phenyl)-3-oxo-piperazine-6-methyl-1-carboxylic acid(3,5-bis-trifluoromethyl-benzyl)-methyl-amide; mixture of synenantiomers

To a solution of intermediate 47 (0.105 g) and triethylamine (0.197 mL)in dry DCM (5 mL) was added drop-wise, at 0° C., a solution oftriphosgene (0.056 g) in dry DCM (3 mL) under inert atmosphere. Thetemperature was maintained at 0° C. for 3 hr, before the addition ofDIPEA (0.3 mL) followed by 3,5-bistrifluoromethyl-methyl-aminehydrochloride (0.166 g). The reaction mixture was stirred at roomtemperature overnight before being diluted with DCM and washed with a 1Nsolution of HCl, H₂O and brine in sequence. The organic phase was driedand the crude product obtained after evaporation of the solvent waspurified by flash chromatography (AcOEt/MeOH 9:1) affording the titlecompound as a foam (0.085 g).

¹H NMR (DMSO) δ (ppm) 8.08 (bt, 1H), 7.95 (s, 1H), 7.63 (s, 2H), 7.13(t, 1H), 6.87 (d, 1H), 6.79 (t, 1H), 5.21 (s, 1H), 4.51 (dd, 2H), 3.64(m, 1H), 3.30 (m, 1H), 3.18 (m, 1H), 2.77 (s, 3H), 2.25 (s, 3H), 1.20(d, 3H).

IR (Nujol) (cm⁻¹) 1675.

MS (m/z): 506 [MH]⁺

Intermediate 49 2-(3,5-Bis-trifluoromethyl-phenyl)-acrylic acid methylester

Palladium tetrakis (triphenylphosphine) (331 g), copper iodide (0.414 g)and 2-tributylstannyl-2-propenoic acid methyl ester (2.82 g) were addedto a solution of 3,5-(bis-trifluoromethyl)iodobenzene (1 g) in dry DMF(10 mL) under a nitrogen atmosphere. The solution was stirred at r.t.for 16 hr, then diluted with water and extracted with AcOEt. The organicextract was dried, concentrated in vacuo and purified by flashchromatography (CH/AcOEt 9:1) to give the title compound (180 mg).

IR (CDCl₃): 1727 (C═O) cm⁻¹.

NMR (DMSO) δ (ppm) 7.95 (s, 1H); 7.89 (s, 1H); 7.87 (s, 1H); 6.6 (s,1H); 6.06 (s, 1H); 3.87 (s, 3H).

Intermediate 501-(3,5-Bis-trifluoromethyl-phenyl)-cyclopropanecarboxylic acid methylester

Sodium hydride (60% suspension in mineral oil-86 mg) was added to asuspension of trimethylsulfoxonium iodide (515 mg) in dry DMF under anitrogen atmosphere. The suspension was stirred at r.t. for 15 min.,then a solution of intermediate 49 (0.58 g) in dry DMF (6 mL) was added.The mixture was stirred at r.t. for 30 min., then it was diluted withbrine and extracted with ethyl acetate. The organic extract was dried,concentrated in vacuo and purified by flash chromatography (CH/AcOEt9:1) to give the title compound (90 mg) as colourless oil.

Intermediate 511-(3,5-Bis-trifluoromethyl-phenyl)-cyclopropanecarboxylic acid

A mixture of intermediate 50 (90 mg) and lithium hydroxide (55.4 mg) inmethanol (10 mL) was heated to reflux for 2 hrs. The organic extract wasconcentrated in vacuo and partitioned between a saturated ammoniumchloride solution and AcOEt. The organic layer was washed with brine,dried and concentrated in vacuo to give the title compound (80 mg) ascolourless oil.

Intermediate 524-[1-(3,5-Bis-trifluoromethyl-phenyl)-cyclopropylcarbamoyl]-3-(S)-(4-fluoro-2-methyl-phenyl)-piperazine-1-carboxylicacid tert-butyl ester

TEA (150 μL) and diphenyphosphorylazide (175 μL) were added to asolution of intermediate 51 (80 mg) in dry toluene (25 mL) previouslycooled to 0° C. under a nitrogen atmosphere. The solution was stirred atr.t. for 3 hr, then intermediate 54 (88 mg) was added and the mixturewas heated to 100° C. for 1 hr. The mixture was allowed to cool to r.t.and partitioned between water and AcOEt. The organic layer was dried,concentrated in vacuo and the residue was purified by flashchromatography (CH/AcOEt 6:4) to give the title compound as a colourlessoil (90 mg).

NMR (DMSO) δ (ppm) 7.75 (bs, 1H), 7.67 (bs, 2H), 7.29 (bs, 1H), 7.18(dd, 1H), 6.96 (dd, 1H), 6.86 (dt, 1H); 5.17 (t, 1H), 3.75-3.42 (m, 5H),3.18 (m, 1H), 2.29 (s, 3H), 1.3 (s, 9H); 1.3-1.1 (m, 4H).

MS: m/z=590 [M+H]⁺.

Intermediate 534-{[1-(3,5-Bis-trifluoromethyl-phenyl)-cyclopropyl]-methyl-carbamoyl}-3-(S)-(4-fluoro-2-methyl-phenyl)-piperazine-1-carboxylicacid tert-butyl ester

Sodium tert-butoxide (38.5 mg) was added to a solution of intermediate52 (80 mg) in dry THF. The solution was stirred at r.t. for 10 min.,then methyl iodide (40 μL) was added and stirring was continued for 1 h.The mixture was partitioned between water and AcOEt. The organic layerwas dried, concentrated in vacuo to give the title compound ascolourless oil (90 mg).

NMR (DMSO) δ (ppm) 7.8 (bs, 1H), 7.38 (dd, 1H), 7.34 (bs, 2H), 6.97 (dd,1H), 6.93 (dt, 1H); 4.5 (bm, 1H), 3.64-2.97 (m, 9H), 2.28 (s, 3H), 1.38(bs, 9H); 1.36-1.24 (2m, 4H).

MS: m/z=604 [M+H]⁺, 626 [M+Na]⁺

Intermediate 541-(Tert-Butoxycarbonyl)-3-(S)-(4-fluoro-2-methyl-phenyl)-piperazine

Di-tert-butyldicarbonate (271 mg) was added to a solution ofintermediate 81 (301 mg) and TEA (315 μL) in DCM (10 mL) previouslycooled to 0° C. under a nitrogen atmosphere. The solution was stirred at0° C. for 40 min., then concentrated in vacuo. The residue waspartitioned between water and AcOEt. The organic layer was washed withbrine, dried and concentrated in vacuo. The residue was purified byflash chromatography (CH/AcOEt 6:4) to give the title compound (80 mg)as a colourless gum.

NMR (d₆-DMSO): δ (ppm) 7.52 (m, 1H); 7.07-6.98 (m, 2H); 3.94-3.74 (m,3H); 3.0-2.5 (m, 4H); 2.33 (s, 3H); 1.4 (s, 9H).

Intermediate 553-(3,5-Bis-trifluoromethyl-benzoyl)-1-vinyl-pyrrolidin-2-one

Trimethylsilyldiazomethane (11.5 mL) was added drop-wise to a solutionof 3,5-bis-(trifluoromethyl)-benzoic acid (2 g) in dry toluene (20 mL)and methanol (0.5 mL) previously cooled to 0° C. under a nitrogenatmosphere. The solution was stirred at r.t. for 1 hr, then concentratedin vacuo to give 3,5-bis-(trifluoromethyl)-benzoic acid methyl ester (2g) as a colourless oil.

A solution of 3,5-bis-(trifluoromethyl)-benzoic acid methyl ester (2 g)and 1-vinyl-2-pyrrolidinone (863 μL) was added to a mixture of sodiumhydride (60% suspension in mineral oil-0.41 g) in dry toluene (30 mL)previously heated to reflux. The mixture was stirred for 12 hrs, then itwas partitioned between saturated ammonium chloride solution and AcOEt.The organic layer was dried, concentrated in vacuo and the residue waspurified by flash chromatography (CH/AcOEt 8:2) to give the titlecompound (1.6 g) as a beige oil.

MS: m/z=352 [M+H]⁺.

Intermediate 565-(3,5-Bis-trifluoromethyl-phenyl)-3,4-dihydro-2H-pyrrole

A solution of intermediate 55 (1.6 g) in THF (30 mL) was added drop-wiseover 1.5 h to a boiling solution of 6N HCl (50 mL) distilling at thesame time the THF. At the end of the addition the distillation apparatuswas removed and reflux was continued for further 4 hrs. The mixture wascooled to 0° C. and a 30% KOH solution was added until pH=12 wasreached. The compound was extracted with DCM (4×10 mL). The combinedorganic extracts were dried, concentrated in vacuo and the residue waspurified by flash chromatography (CH/AcOEt 7:3) to give the titlecompound (100 mg) as pale yellow oil.

NMR (DMSO) δ (ppm) 8.38 (s, 2H); 8.22 (s, 1H); 4.0 (t, 2H), 3.03 (tt,2H); 1.99 (m, 2H).

MS: m/z=282 [M+H]⁺.

Intermediate 57 2-(3,5-Bis-trifluoromethyl-phenyl)-pyrrolidine

Sodium borohydride (1.5 eq) was added to a solution of intermediate 56(100 mg) in methanol (5 mL) previously cooled to 0° C. under a nitrogenatmosphere. The solution was diluted with water and extracted withAcOEt. The organic extract was dried and concentrated in vacuo to givethe title compound (103 mg) as a pale yellow oil.

Intermediates 584-[2-(3,5-Bis-trifluoromethyl-phenyl)-pyrrolidine-1-carbonyl]-3-(S)-(4-fluoro-2-methyl-phenyl)-piperazine-1-carboxylicacid tert-butyl ester (58 a Enantiomer A)4-[2-(3,5-Bis-trifluoromethyl-phenyl)-pyrrolidine-1-carbonyl]-3-(S)-(4-fluoro-2-methyl-phenyl)-piperazine-1-carboxylicacid tert-butyl ester (58 b enantiomer B)

A solution of triphosgene (47 mg) in DCM (2 mL) was added drop-wise to asolution of intermediate 54 (103 mg) and TEA (97 μL) in acetonitrile (3mL) previously cooled to 0° C. under a nitrogen atmosphere. The solutionwas stirred at r.t. for 2 hr, then intermediate 56 (103 mg) was addedand the solution was heated to reflux for 5 hrs. After cooling to r.t.,the solution was diluted with water and extracted with AcOEt. Theorganic layer was was dried, concentrated in vacuo and the residue waspurified by flash chromatography (CH/AcOEt from 8:2 to 7:3) to give thetitle compound 58a (15 mg) and the title compound 58b (20 mg).

Intermediate 59 2-(3,5-Bis-trifluoromethyl-phenyl)-pent-4-enoic acid

Butyl lithium (1.6 M in hexane-1.7 mL) was added to a solution ofdiisopropylamine (4.88 g) in dry THF (40 mL) previously cooled to −78°C. under a nitrogen atmosphere. The solution was allowed to warm to 0°C. and stirred at this temperature for 1 h. Next, the solution wascooled to −78° C. and a solution of3,5-(bis-trifluoromethyl)-phenylacetic acid (3 g) in THF (10 mL) wasadded. The solution was allowed to warm to 0° C. and stirred at thistemperature for 2 h. The solution was cooled again to −78° C. and2-propenyl iodide (1.2 mL) was added. The solution was allowed to warmto r.t. and stirred at r.t. for 3 hrs. The solution was quenched with 5NHCl until pH=2 and extracted with AcOEt. The organic layer was dried,concentrated in vacuo and the residue was purified by flashchromatography (CH/AcOEt 75:25) to give the title compound (2.4 g) asyellow oil.

Intermediates 604-[1-(3,5-Bis-trifluoromethyl-phenyl)-but-3-enylcarbamoyl]-3-(S)-(4-fluoro-2-methyl-phenyl)-piperazine-1-carboxylicacid tert-butyl ester (60a enantiomer A)4-[1-(3,5-Bis-trifluoromethyl-phenyl)-but-3-enylcarbamoyl]-3-(S)-(4-fluoro-2-methyl-phenyl)-piperazine-1-carboxylicacid tert-butyl ester (60b enantiomer B)

TEA (885 μL) and diphenyphosphorylazide (1.3 g) were added to a solutionof intermediate 59 (500 mg) in dry toluene (25 mL) previously cooled to0° C. under a nitrogen atmosphere. The solution was stirred at r.t. for3 hr, then 54 (521 mg) was added and the mixture was heated to 100° C.for 1 hr. The mixture was allowed to cool to r.t. and partitionedbetween water and AcOEt. The organic layer was dried, concentrated invacuo and the residue was purified by flash chromatography (CH/AcOEtfrom 8:2 to 7:3) to give the title compound 60a (480 mg) and the titlecompound 60b (450 mg) as white foams.

Intermediate 60a NMR (DMSO) δ (ppm) 7.94 (s, 2H); 7.84 (s, 1H); 7.14 (t,1H); 6.94 (dd, 1H), 6.84 (dt, 1H); 6.66 (d, 1H); 5.62 (m, 1H); 5.18 (t,1H); 5.0-4.9 (m, 2H), 4.84 (m, 1H); 3.82 (dt, 1H); 3.75 (m, 1H); 3.65(bd, 1H); 3.43 (bt, 1H); 3.52 (dd, 1H); 3.17 (m, 1H); 2.45 (t, 2H), 2.24(s, 3H); 1.29 (m, 1H).

Intermediate 60b NMR (DMSO) δ (ppm) 7.84 (s, 2H); 7.81 (s, 1H); 7.14 (t,1H); 6.97 (dd, 1H), 6.86 (dt, 1H); 6.53 (bd, 1H); 5.66 (m, 1H); 5.15 (t,1H); 5.05-4.9 (m, 3H), 3.89 (dt, 1H); 3.75-3.65 (b, 1H); 3.63 (bd, 1H);3.52 (dd, 1H); 3.43 (dt, 1H); 3.2 (m, 1H); 2.5 (t, 2H), 2.3 (s, 3H);1.28 (m, 1H).

Intermediate 614-{2-propenyl-[1-(3,5-Bis-trifluoromethyl-phenyl)-but-3-enyl]-carbamoyl}-3-(S)-(4-fluoro-2-methyl-phenyl)-piperazine-1-carboxylicacid tert-butyl ester (enantiomer A)

Sodium tert-butoxide (245 mg) was added to a solution of intermediate60a (480 mg) in dry THF (20 mL). The solution was stirred at r.t. for 10min., then 2-propenyl iodide (400 μL) was added and stirring wascontinued for 3 h. The mixture was partitioned between water and AcOEt.The organic layer was dried and concentrated in vacuo to give the titlecompound as colourless oil (540 mg).

NMR (DMSO) δ (ppm) 7.94 (s, 1H); 7.79 (s, 2H); 7.28 (dd, 1H); 6.98 (dd,1H), 6.84 (dt, 1H); 5.63 (m, 1H); 5.46 (m, 1H); 5.18 (t, 1H); 5.14-4.9(m, 4H), 4.4 (bd, 1H); 3.98 (dd, 1H); 3.86 (dd, 1H); 3.7-3.55 (m, 2H);3.4-2.7 (m, 4H); 2.32 (s, 3H), 1.36 (s, 9H).

Intermediate 624-[2-(3,5-Bis-trifluoromethyl-phenyl)-3,6-dihydro-2H-pyridine-1-carbonyl]-3-(S)-(4-fluoro-2-methyl-phenyl)-piperazine-1-carboxylicacid tert-butyl ester (enantiomer A)

Benzylidene bis(tricyclohexylphosphine)dichlororuthenium (34 mg) wasadded to a solution of intermediate 61 (540 mg) in dry DCM (20 mL) undera nitrogen atmosphere. The solution was stirred at r.t. for 4 hrs, thenit was diluted with a saturated ammonium chloride solution and extractedwith AcOEt. The organic layer was dried, concentrated in vacuo and theresidue was purified by flash chromatography (CH/AcOEt 75:25) to givethe title compound (0.35 g) as a brown oil.

NMR (DMSO) δ (ppm) 7.87 (s, 1H); 7.74 (s, 2H); 7.29 (dd, 1H); 6.93 (dd,1H), 6.81 (dt, 1H); 5.8-5.6 (m, 2H); 5.2-4.9 (m, 4H); 4.7 (t, 1H); 4.46(bs, 1H); 4.0-2.73 (m, 10H); 2.31 (s, 3H), 1.38 (s, 9H).

Intermediate 631-(Tert-Butoxycarbonyl)-3-(4-fluoro-2-methyl-phenyl)-piperazine

Di-tert-butyldicarbonate (271 mg) was added to a solution ofintermediate 7 (301 mg) and TEA (315 μL) in DCM (10 mL) previouslycooled to 0° C. under a nitrogen atmosphere. The solution was stirred at0° C. for 40 min., then concentrated in vacuo. The residue waspartitioned between water and AcOEt. The organic layer was washed withbrine, dried and concentrated in vacuo. The residue was purified byflash chromatography (CH/AcOEt 6:4) to give the title compound (80 mg)as a colourless gum.

NMR (d₆-DMSO): δ (ppm) 7.52 (m, 1H); 7.07-6.98 (m, 2H); 3.94-3.74 (m,3H); 3.0-2.5 (m, 4H); 2.33 (s, 3H); 1.4 (s, 9H).

Intermediate 644-{[1-(3,5-Bis-trifluoromethyl-phenyl)-but-3-enyl]-carbamoyl}-3-(4-fluoro-2-methyl-phenyl)-piperazine-1-carboxylicacid tert-butyl ester (64a diastereoisomer A)4-[1-(3,5-Bis-trifluoromethyl-phenyl)-but-3-enylcarbamoyl]-3-(4-fluoro-2-methyl-phenyl)-piperazine-1-carboxylicacid tert-butyl ester (64b diastereoisomer B)

TEA (700 μL) and diphenyphosphorylazide (812 μL) were added to asolution of intermediate 59 (400 mg) in dry toluene (20 mL) previouslycooled to 0° C. under a nitrogen atmosphere. The solution was stirred atr.t. for 3 hr, then 400 mg of intermediate 63 was added and the mixturewas heated to 100° C. for 1 hr. The mixture was allowed to cool to r.t.and partitioned between water and AcOEt. The organic layer was dried,concentrated in vacuo and the residue was purified by flashchromatography (CH/AcOEt 8:2) to give the title compound 64a (340 mg)and the title compound 64 b (250 mg).

Intermediate 64a NMR (DMSO) δ (ppm) 7.94 (s, 2H); 7.84 (s, 1H); 7.14 (t,1H); 6.94 (dd, 1H), 6.84 (dt, 1H); 6.66 (d, 1H); 5.62 (m, 1H); 5.18 (t,1H); 5.0-4.9 (m, 2H), 4.84 (m, 1H); 3.82 (dt, 1H); 3.75 (m, 1H); 3.65(bd, 1H); 3.43 (bt, 1H); 3.52 (dd, 1H); 3.17 (m, 1H); 2.45 (t, 2H), 2.24(s, 3H); 1.29 (m, 1H).

Intermediate 64b NMR (DMSO) δ (ppm) 7.84 (s, 2H); 7.81 (s, 1H); 7.14 (t,1H); 6.97 (dd, 1H), 6.86 (dt, 1H); 6.53 (bd, 1H); 5.66 (m, 1H); 5.15 (t,1H); 5.05-4.9 (m, 3H), 3.89 (dt, 1H); 3.75-3.65 (b, 1H); 3.63 (bd, 1H);3.52 (dd, 1H); 3.43 (dt, 1H); 3.2 (m, 1H); 2.5 (t, 2H), 2.3 (s, 3H);1.28 (m, 1H).

Intermediate 654-{[1-(3,5-Bis-trifluoromethyl-phenyl)-but-3-enyl]-methyl-carbamoyl}-3-(4-fluoro-2-methyl-phenyl)-piperazine-1-carboxylicacid tert-butyl ester (diastereoisomer A)

Sodium tert-butoxide (28 mg) was added to a solution of intermediate 64a(70 mg) in dry THF (10 mL). The solution was stirred at r.t. for 30min., then methyl iodide (37 μL) was added. Reaction was slow, thusfurther amount of sodium tert-butoxide (28 mg) and methyl iodide (37 μL)were added (2×) and stirring was continued for 18 h. The mixture waspartitioned between water and AcOEt. The organic layer was dried,concentrated in vacuo and the residue was purified by flashchromatography (CH/AcOEt 8:2) to give the title compound as colourlessoil (44 mg).

NMR (DMSO) δ (ppm) 7.91 (bs, 1H); 7.68 (bs, 2H); 7.22 (dd, 1H); 6.94(dd, 1H), 6.78 (dt, 1H); 5.72 (m, 1H); 5.34 (dd, 1H); 5.2-5.06 (2m, 2H),4.41 (dd, 1H); 3.69 (m, 1H); 3.3-2.75 (m, 9H); 2.32 (s, 3H), 1.4 (s,9H).

Intermediate 664-{Methyl-[1-(3,5-Bis-trifluoromethyl-phenyl)-but-3-enyl]-carbamoyl}-3-(4-fluoro-2-methyl-phenyl)-piperazine-1-carboxylicacid tert-butyl ester (diastereoisomer B)

Sodium tert-butoxide (28 mg) was added to a solution of intermediate 64b(70 mg) in dry THF (10 mL). The solution was stirred at r.t. for 30min., then methyl iodide (37 μL) was added. Reaction was slow, thusfurther amount of sodium tert-butoxide (28 mg) and methyl iodide (37 μL)were added (2×) and stirring was continued for 18 h. The mixture waspartitioned between water and AcOEt. The organic layer was dried,concentrated in vacuo and the residue was purified by flashchromatography (CH/AcOEt 8:2) to give the title compound as colourlessoil (44 mg).

NMR (DMSO) δ (ppm) 7.91 (bs, 1H); 7.81 (bs, 2H); 7.25 (m, 1H); 6.94 (m,1H), 6.84 (m, 1H); 5.62 (m, 1H); 5.14-4.94 (m, 2H); 5.11 (t, 1H); 4.46(m, 1H); 3.7 (dd, 2H); 3.65-3.32 (m, 2H); 3.3 (m, 1H); 3.0 (m, 1H); 2.76(m, 2H); 2.76 (s, 3H), 2.31 (s, 3H); 1.39 (s, 9H).

Intermediate 674-{2-propenyl-[1-(3,5-Bis-trifluoromethyl-phenyl)-but-3-enyl]-carbamoyl}-3-(4-fluoro-2-methyl-phenyl)-piperazine-1-carboxylicacid tert-butyl ester (diastereoisomer A)

Sodium tert-butoxide (113 mg) was added to a solution of intermediate 64a (220 mg) in dry THF (15 mL). The solution was stirred at r.t. for 10min., then 2-propenyl iodide (186 μL) was added and stirring wascontinued for 3 h. The mixture was partitioned between water and AcOEt.The organic layer was dried and concentrated in vacuo to give the titlecompound as colourless oil (180 mg).

NMR (DMSO) δ (ppm) 7.94 (s, 1H); 7.78 (s, 2H); 7.27 (dd, 1H); 6.97 (dd,1H), 6.84 (dt, 1H); 5.62 (m, 1H); 5.45 (m, 1H); 5.17 (t, 1H); 5.08 (d,1H); 5.04 (d, 1H); 4.99 (d, 1H), 4.93 (d, 1H); 4.38 (m, 1H); 3.95 (m,1H); 3.85 (dd, 1H); 3.61 (m, 2H); 3.34 (m, 2H); 3.08 (m, 2H); 2.66 (m,2H); 2.31 (s, 3H), 1.35 (s, 9H).

Intermediate 684-[2-(3,5-Bis-trifluoromethyl-phenyl)-3,6-dihydro-2H-pyridine-1-carbonyl]-3-(4-fluoro-2-methyl-phenyl)-piperazine-1-carboxylicacid tert-butyl ester (diastereoisomer A)

Benzylidene bis(tricyclohexylphosphine)dichlororuthenium (5% in mol 7.7mg) was added to a solution of intermediate 67 (120 mg) in dry DCM (5mL) under a nitrogen atmosphere. The solution was stirred at r.t. for 4hrs, then it was diluted with a saturated ammonium chloride solution andextracted with AcOEt. The organic layer was dried, concentrated in vacuoand the residue was purified by flash chromatography (CH/AcOEt 7:3) togive the title compound (85 g) as a brown oil.

NMR (DMSO) δ (ppm) 7.9 (s, 1H); 7.69 (s, 2H); 7.26 (dd, 1H); 6.95 (dd,1H), 6.82 (dt, 1H); 5.89 (m, 1H); 5.68 (bd, 1H); 5.28 (d, 1H); 4.49 (dd,4H); 4.2 (d, 1H); 3.69 (dd, 1H); 3.64 (m, 1H); 3.32 (m, 2H); 3.31 (m,1H); 3.1 (m, 1H); 2.7 (bd, 1H); 2.53 (m, 1H); 2.3 (s, 3H), 1.37 (s, 9H).

Intermediate 69 2-(3,5-Bis-trifluoromethyl-phenyl)-2-methyl-propionicacid methyl ester

(Trimethylsilyl)diazomethane (2M in hexane-3.68 mL) was added drop-wiseto a solution of (3,5-bis-trifluoromethyl-phenyl)-acetic acid (500 mg)and dry methanol (82 μL) in dry toluene (8 mL) at 0° C., under anitrogen atmosphere. The reaction mixture was stirred at 0° C. for 5minutes, then the solvent was evaporated in vacuo to obtain the(3,5-bis-trifluoromethyl-phenyl)-acetic acid, methyl ester a pale yellowoil (440 mg). This material was dissolved in dry THF (4.5 mL) at 0° C.,under nitrogen atmosphere and sodium bis(trimethylsilyl) amide (1.0M inTHF-4 mL) was added dropwise. After ten minutes, methyl iodide (958 μL)was added and the reaction mixture was stirred at r.t. for 2 hours. Thereaction was quenched with a 2N hydrochloric acid solution (7 mL) andthe product was extracted with diethyl ether (2×10 mL). The combinedorganic extracts were dried and concentrated in vacuo to a residue whichwas purified by flash chromatography (CH/AcOEt 95:5) to give the titlecompound (184 mg) as a colourless oil.

NMR (d₆-DMSO): δ (ppm) 8.05 (s, 1H); 7.9 (s, 2H); 3.6 (s, 3H); 1.6 (s,6H).

Intermediate 70 2-(3,5-Bis-trifluoromethyl-phenyl)-2-methyl-propionicacid

A solution of 2-(3,5-bis-trifluoromethyl-phenyl)-2-methyl-propionicacid, methyl ester (intermediate 69-184 mg) and potassium hydroxide (131mg) in MeOH (2.5 mL) was heated to reflux for 1 hour, then it wasallowed to cool to r.t. and acidified to pH=3 with 10% hydrochloric acidsolution and extracted with AcOEt (2×10 mL). The combined organicextracts were dried and concentrated in vacuo to a residue which waspurified by flash chromatography (CH/AcOEt from 8:2 to 6:4) to give thetitle compound (141 mg) as a white solid.

NMR (d₆-DMSO): δ (ppm) 8.05 (s, 1H); 7.9 (s, 2H); 1.6 (s, 6H).

Intermediate 711-(Benzyloxycarbonyl)-3-(S)-(4-fluoro-2-methyl-phenyl)-piperazine

Borane THF (23.16 mL) was added to a solution of intermediate 39 (964mg) in dry THF (3 mL) previously cooled to 0° C. under a nitrogenatmosphere. The mixture was heated to 80° C. for 4 hrs. MeOH (4 mL) wasadded and the mixture was concentrated in vacuo. The residue was treatedwith HCl in Et₂O (38 mL) and the solution was heated to 45° C. for 1 hr.The mixture was filtered to give2-(S)-(4-fluoro-2-methyl-phenyl)-piperazine dihydrochloride (944 mg).

A solution of benzylchloroformate (376 μL) in dry DCM (20 mL) was addeddrop-wise to a solution of the2-(S)-(4-fluoro-2-methyl-phenyl)-piperazine dihydrochloride (700 mg) andTEA (1.1 mL) in DCM (30 mL) previously cooled to 0° C. under a nitrogenatmosphere. The mixture was stirred at r.t. for 2 hrs, then washed withbrine. The organic layer was dried, concentrated in vacuo and theresidue was purified by flash chromatography (from CH/AcOEt 1:1 to AcOEt100%) to give the title compound (750 mg) as colourless oil.

NMR (d₆-DMSO): δ (ppm) 7.51 (dd, 1H); 7.36-7.28 (m, 5H); 6.95 (m, 2H);5.1 (dd, 2H); 3.92 (m, 2H); 3.74 (dd, 1H); 2.95 (dd, 1H); 2.91 (dt, 1H);2.72 (dt, 1H); 2.62 (t, 1H); 2.29 (s, 3H).

Intermediate 724-[1-(3,5-Bis-trifluoromethyl-phenyl)-1-methyl-ethylcarbamoyl]-3-(S)-(4-fluoro-2-methyl-phenyl)-piperazine-1-carboxylicacid benzyl ester

TEA (145 μL) and diphenyphosphorylazide (169 μL) were added to asolution of intermediate 70 (96 mg) in dry toluene (1.5 mL) previouslycooled to 0° C. under a nitrogen atmosphere. The solution was stirred atr.t. for 3 hr, intermediate 71 (96 mg) was added and the mixture washeated to 100° C. for 1 hr. The mixture was allowed to cool to r.t. andpartitioned between water and AcOEt. The organic layer was dried,concentrated in vacuo and the residue was purified by flashchromatography (CH/AcOEt 7:3) to give the title compound (140 mg) as apale yellow gum.

NMR (d₆-DMSO): δ (ppm) 7.8 (s, 2H); 7.78 (s, 1H); 7.38-7.22 (m, 5H);7.21 (dd, 1H); 6.95 (dd, 1H); 6.84 (dt, 1H); 6.52 (s, 1H); 5.18 (t, 1H);5.05 (s, 2H); 3.89 (dt, 1H); 3.79 (dd, 1H); 3.72 (dt, 1H); 3.57 (dd,1H); 3.44 (dt, 1H); 3.28 (bt, 1H); 2.23 (s, 3H); 1.55 (s, 3H); 1.5 (s,3H).

MS: m/z=626 [MH]⁺.

Intermediate 734-{[1-(3,5-Bis-trifluoromethyl-phenyl)-1-methyl-ethyl]-methyl-carbamoyl}-3-(S)-4-fluoro-2-methyl-phenyl)-piperazine-1-carboxylicacid benzyl ester

Sodium tert-butoxide (53 mg) was added to a solution of intermediate 72(140 mg) in dry THF (1.5 mL). The solution was stirred at r.t. for 30min., then methyl iodide (69 μL) was added and stirring was continuedfor 18 hrs. Further sodium tert-butoxide (42 mg) and methyl iodide (140μL) were added and the mixture was heated to 70° C. for 3 hrs and thenallowed to stir at r.t. for 18 hrs. The mixture was partitioned betweenwater and AcOEt (2×10 mL). The organic layer was dried, concentrated invacuo and the residue was purified by flash chromatography (CH/AcOEt9:1) to give the title compound as colourless gum (58 mg).

NMR (d₆-DMSO): δ (ppm) 7.81 (s, 2H); 7.78 (s, 1H); 7.32-7.25 (m, 6H);6.9 (dd, 1H); 6.85 (td, 1H); 5.08 (s, 2H); 4.64 (dd, 1H); 3.58 (m, 3H);3.43 (m, 3H); 3.0 (s, 3H); 2.18 (s, 3H); 1.57 (s, 3H); 1.51 (s, 3H).

MS: m/z=640 [MH]⁺.

Intermediate 74 2-(3,5-Bis-trifluoromethyl-phenyl)-3-methyl-butyric acidmethyl ester

Sodium bis(trimethylsilyl) amide (1.0M in THF-177 μL) was addeddrop-wise to a solution of (3,5-bis-trifluoromethyl-phenyl)-acetic acidmethyl ester (389 mg) in dry THF (2 mL) at 0° C., under nitrogenatmosphere. After ten minutes, isopropyl iodide (143 μL) was added andthe reaction mixture was stirred at 0° C. for 30 min. Further isopropyliodide (143 μL) was added and the solution stirred at r.t. for 1 hour.The reaction was quenched with a 2N hydrochloric acid solution (2 mL)and the product was extracted with Et₂O (2×). The combined organicextracts were dried and concentrated in vacuo to a residue which waspurified by flash chromatography (CH/AcOEt 95:5) to give the titlecompound (184 mg) as a colourless oil.

NMR (d₆-DMSO): δ (ppm) 8.05 (bs, 3H); 3.76 (d, 1H); 3.67 (s, 3H); 2.33(m, 1H); 1.01 (d, 3H); 0.69 (d, 3H).

MS: m/z=328 [M]⁺.

Intermediate 75 2-(3,5-Bis-trifluoromethyl-phenyl)-3-methyl-butyric acid

A solution of intermediate 74 (280 mg) and potassium hydroxide (191 mg)in MeOH (4 mL) was heated to reflux for 1 hour, then it was allowed tocool to r.t. and acidified to pH=3 with 10% hydrochloric acid solutionand extracted with AcOEt (2×10 mL). The combined organic extracts weredried and concentrated in vacuo to give the title compound (250 mg) as awhite solid.

NMR (d₆-DMSO): δ (ppm) 8.05 (bs, 3H); 3.76 (d, 1H); 2.32 (m, 1H); 1.01(d, 3H); 0.65 (d, 3H).

Intermediate 764-[1-(3,5-Bis-trifluoromethyl-phenyl)-2-methyl-propylcarbamoyl]-3-(4-fluoro-2-methyl-phenyl)-piperazine-1-carboxylicacid tert-butyl ester

TEA (133 μL) and diphenyphosphorylazide (156 μL) were added to asolution of intermediate 75 (78 mg) in dry toluene (1 mL) previouslycooled to 0° C. under a nitrogen atmosphere. The solution was stirred atr.t. for 3 hr, then intermediate 63 (80 mg) was added and the mixturewas heated to 100° C. for 2 hr. The mixture was allowed to cool to r.t.and partitioned between water and AcOEt. The organic layer was dried,concentrated in vacuo and the residue was purified by flashchromatography (CH/THF 7:3) to give the title compound (140 mg) as ayellow gum.

IR (nujol) 3400 (NH), 1699 (C═O) cm⁻¹.

NMR (d₆-DMSO): δ (ppm) 7.93 (s, 1H+1H); 7.84 (s, 2H); 7.78 (s, 2H); 7.13(dd, 1H+1H); 6.95 (dd, 1H+1H); 6.83 (m, 1H+1H); 6.51 (d, 1H); 6.41 (d,1H); 5.2 (t, 1H); 5.16 (t, 1H); 4.57 (t, 1H); 4.48 (t, 1H); 3.9-3.17 (m,6H+6H); 2.3 (s, 3H); 2.24 (s, 3H); 2.0-1.96 (m, 1H+1H); 1.28-1.27 (d,9H+9H); 0.87 (d, 3H); 0.74 (d, 3H); 0.64 (d, 3H); 0.62 (d, 3H).

MS: m/z=606 [MH]⁺.

Intermediate 774-{[1-(3,5-Bis-trifluoromethyl-phenyl)-2-methyl-propyl]-methyl-carbamoyl]}-3-(4-fluoro-2-methyl-phenyl)-piperazine-1-carboxylicacid tert-butyl ester (77a diastereoisomer A)4-{[1-(3,5-Bis-trifluoromethyl-phenyl)-2-methyl-propyl]-methyl-carbamoyl]}-3-(4-fluoro-2-methyl-phenyl)-piperazine-1-carboxylicacid tert-butyl ester (77b diastereoisomer B)

Sodium tert-butoxide (55 mg) was added to a solution of intermediate 76(140 mg) in dry THF (1.5 mL). The solution was stirred at r.t. for 30min., then methyl iodide (72 μL) was added and stirring was continuedfor 18 hrs. Further sodium tert-butoxide (55 mg) and methyl iodide (72μL) were added and the mixture was stirred at r.t. for 3 hrs. Themixture was partitioned between water and AcOEt (2×). The organic layerwas dried, concentrated in vacuo and the residue was purified by flashchromatography (CH/AcOEt 9:1) to give the title compound 77a (35 mg) andthe title compound 77 b (37 mg) as colourless gum.

Intermediate 77a: T.l.c.: CH/AcOEt 8:2 Rf=0.62

NMR (d₆-DMSO): δ (ppm) 8.0 (s, 1H); 7.91 (bs, 2H); 7.21 (m, 1H);6.95-6.83 (m, 2H); 4.65 (bm, 1H); 4.25 (bm, 1H); 3.68 (m, 2H); 3.25-2.81(m+m+s, 7H); 2.32 (s, 3H); 1.38 (s, 9H); 0.68 (d, 3H); 0.64 (d, 3H).

MS: m/z=620 [MH]⁺.

Intermediate 77 b: T.l.c.: CH/AcOEt 8:2 Rf=0.62

T.l.c.: CH/AcOEt 8:2 Rf=0.73

NMR (d₆-DMSO): δ (ppm) 7.96 (bs, 1H); 7.79 (bs, 2H); 6.99 (m, 1H); 6.93(m, 1H); 6.6 (m, 1H); 4.87 (d, 1H); 4.27 (m, 1H); 3.7-3.2 (bm+bm+s+s,10H); 1.39 (s, 9H); 0.88 (d, 3H); 0.73 (d, 3H).

MS: m/z=620 [MH]⁺.

Intermediate 78 (3,5-Bis-trifluoromethyl-benzylidene)-methylamine

A solution of 3,5-bis(trifluoromethyl)-benzaldehyde (412 μL) in dry THF(5 mL) was added dropwise to a solution of methylamine (2M in MeOH-3.12mL) in dry THF (5 mL) at 23° C. under a nitrogen atmosphere. Thereaction mixture was stirred overnight, then the solvent was evaporatedin vacuo to give the title compound (385 mg) as a colourless oil.

NMR (CDCl₃): δ (ppm) 8.4 (s, 1H); 8.2 (s, 2H); 7.9 (s, 1H); 3.6 (s, 3H).

Intermediate 79[(3,5-Bis-trifluoromethyl-phenyl)-cyclopropyl-methyl]-methylamine

A solution of cyclopropyl bromide (518 μL) in dry diethyl ether (15 mL)was added dropwise to magnesium turnings (186 mg) previously heated to40° C. under a nitrogen atmosphere. The reaction mixture was refluxedfor 2 hours, then allowed to cooled to r. t. and decanted from theexcess of magnesium. The cyclopropyl magnesium bromide so obtained, wasadded to a suspension of copper iodide (614 mg) in dry THF (5 mL)previously cooled to −50° C. under a nitrogen atmosphere. The reactionmixture was stirred at −50° C. for 20 min, then the temperature wastaken to −78° C. and boron trifluoride etherate (408 μL) was added.After 5 minutes, intermediate 78 (330 mg) was added dropwise and thereaction mixture was stirred at −50° C. for 3 hours. The reaction wasquenched with a mixture of ammonia (30% in water-10 mL) and saturatedammonium chloride solution (10 mL), extracted with petroleum ether (2×20mL) and concentrated in vacuo. Then, 1N hydrochloric acid solution wasadded until pH=3, the aqueous phase was washed with petroleum ether(2×20 mL), then basified with solid potassium hydroxide until pH=9.After extraction with AcOEt (2×20 mL), the organic layer was dried andconcentrated in vacuo to give the title compound (126 mg) as a paleyellow oil.

NMR (d₆-DMSO): δ (ppm) 8.03 (s, 2H); 7.94 (s, 1H); 2.96 (d, 1H); 2.4(bs, 1H); 2.11 (s, 3H); 0.92 (m, 1H); 0.54 (m, 1H); 0.38 (m, 1H); 0.29(t, 2H).

MS (ES/+): m/z=298 [MH]+

Intermediate 804-{[(3,5-Bis-trifluoromethyl-phenyl)-cyclopropyl-methyl]-methyl-carbamoyl}-3-(4-fluoro-2-methyl-phenyl)-piperazine-1-carboxylicacid tert-butyl ester(diastereoisomer A)

A solution of triphosgene (45 mg) in dry DCM (0.5 mL) was addeddrop-wise to a solution of intermediate 63 (100 mg) and TEA (95 μL) indry DCM (1.5 mL) previously cooled to 0° C. under a nitrogen atmosphere.The reaction mixture was stirred at 0° C. for 2 hours, then, a solutionof and DIPEA (237 μL) in dry acetonitrile (2 mL) was added. The reactionwas heated to 70° C. in order to evaporate the DCM, then intermediate 79(110 mg) was added and the reaction mixture was refluxed overnight. Themixture was diluted with AcOEt (10 mL), washed with a 2N hydrochloricacid solution (10 mL) and brine (10 mL), dried and concentrated in vacuoto a residue, which was purified by flash chromatography (CH/AcOEt from8:2 to 7:3) to yield the title compound (10 mg)

NMR (d₆-DMSO): δ (ppm) 7.77 (s, 1H); 7.73 (s, 2H); 7.24 (m, 1H); 6.85(m, 2H); 4.56 (d, 1H); 4.46 (bm, 1H); 3.94 (m, 2H); 3.23 (m, 2H); 3.05(m, 2H); 2.96 (s, 3H); 2.4 (s, 3H); 1.47 (s, 9H); 1.25 (m, 1H); 0.84 (m,1H); 0.43 (m, 2H); 0.18 (m, 1H).

Intermediate 81 (S)-3-(4-Fluoro-2-methyl-phenyl)-piperazinedihydrochloride

To a solution of intermediate 39 (60.35 g) in dry THF (180 ml), at 0-3°C., under N₂, BH₃.THF 1M/THF (1220 mL) was added dropwise. The solutionwas refluxed for 4 hours then cooled to 0-3° C. and methanol (240 mL)was added. The reaction mixture was heated to room temperature then itwas concentrated to dryness. The residue was redissolved in methanol(603.5 mL), excess HCl 1N in Et₂O (1207 mL) was added and the mixturewas refluxed for 2 hours then cooled at 3° C. for 4 hours. Thesuspension was filtered to obtain a white solid that was washed withEt₂O (60.35 mL) and dried to yield the title compound (72.02 g)

¹H-NMR (DMSO) δ (ppm) 11.0-9.5 (b, 4H); 7.99-7.19 (dd-m, 3H); 4.96 (dd,1H); 3.65-3.15 (m, 6H); 2.42 (s, 3H).

Intermediate 82(R)-[(3,5-bis-trifluoromethyl-phenyl)-ethyl]-methyl-amine

To a solution of 3,5-bis-trifluoromethylacetophenone (300 g) in MeOH(1120 mL), a solution of methylamine 8M in EtOH (372 mL) was addeddropwise during 15 min. at 25° C. under N₂. The mixture was stirred for24 hrs at 25° C. under N₂. Then, NaBH₄ was portionwise added over 30 min(27.9 g) at 0° C. A second amount of NaBH₄ was added over 30 min (17.1g) and the mixture stirred for further 1.5 hrs.

The mixture was concentrated by evaporating 600 mL of solvent undervacuum then it was slowly poured into a mixture of AcOEt (1500 mL)/NH₄Clsat (750 mL) and water (750 mL). The water phase was back-extracted withAcOEt (1500 mL). The combined organic phases were washed withWater/Brine (150 mL/150 mL) then evaporated to obtain[(3,5-bis-trifluoromethyl-phenyl)-ethyl]-methyl-amine (305 g) as ayellow oil

To a solution of [(3,5-bis-trifluoromethyl-phenyl)-ethyl]-methyl-amine(245.6 g) in EtOAc (2380 mL), L(−) malic was added portionwise (118 g).

The suspension was stirred for 2 hrs at 25° C. then 3 hrs at 0° C. Thesuspension was filtered and the cake was washed with EtOAc (240 mL). Thesolid was dried under vacuum obtaining crudeL(−)malate[(3,5-bis-trifluoromethyl-phenyl)-ethyl]-methyl-amine (135.3g) as a white solid which was suspended in Ethyl acetate (1760 mL) thenheated to reflux till complete dissolution and then cooled at 25° C. Thesuspension was filtered, washed with Ethyl acetate (135 mL) then driedto obtainL(−)malate[(3,5-bis-trifluoromethyl-phenyl)-ethyl]-methyl-amine (128.5g). The solid was stirred in a mixture of NaOH 10% v/v (720 mL) andEthyl acetate (650 mL). Organic phase was washed with water (720 mL),then concentrated to yield the title compound (82.2 g).

¹H-NMR (DMSO) δ (ppm) 7.99 (s, 2H); 7.85 (s, 1H); 3.78 (q, 1H); 2.34 (s,1H); 2.09 (s, 3H); 1.23 (d, 3H).

EXAMPLE 1 2-(4-Fluoro-2-methyl-phenyl)-piperazine-1-carboxylic acid(3,5-bistrifluoromethyl-benzyl)-methyl-amide hydrochloride

A solution of intermediate 13 (0.05 g) in EtOH (10 mL) was hydrogenatedat atmospheric pressure for 3 hr, in the presence of 10% Pd/C (10 mg) ascatalyst. The catalyst was filtered off and the solvent was evaporated.The crude residue dissolved in diethyl ether and then a 1M sol. of HClin Et₂O (0.1 mL) was added. The formed precipitate was filtered andwashed with diethyl ether to obtain the title compound (0.02 g) as awhite powder.

m.p.>220° C.

NMR (DMSO) δ (ppm) 9.33 (bm, 1H), 9.18 (bm, 1H), 7.96 (s, 1H), 7.59 (s,2H), 7.33 (dd, 1H), 6.99 (d, 1H), 6.85 (t, 1H), 4.63 (d, 1H), 4.53 (d,1H), 4.37 (d, 1H), 3.52 (d, 1H), 3.4-3.2 (m, 2H), 3.25 (m, 1H), 3.04 (t,1H), 3.0-2.8 (m, 1H), 2.93 (s, 3H), 2.38 (s, 3H).

IR (Nujol) (cm⁻¹) 3200, 1659

MS (m/z) 478 [M−Cl]⁺

EXAMPLE 2 2-(3-Isopropyl-phenyl)-piperazine-1-carboxylic acid(3,5-bis-trifluoromethyl-benzyl)-methyl-amide hydrochloride

To a solution of intermediate 14 (0.353 g) in anh. EtOH (5.7 mL), atr.t., under N₂, Pd/C 10% (175 mg, 50% wt) was added. The blacksuspension was placed under an atmosphere of H₂ and was stirred for 3hr. The catalyst was then filtered on Celite and the Celite cake wasrinsed with EtOH. HCl 1.0M in Et₂O was then added (1.13 mL). The solventwas evaporated and the oil obtained was triturated with Et₂O. The solidwas filtered, rinsed with Et₂O and dried under vacuum. The titlecompound was obtained as a grey solid (104 mg).

m.p. 77-80° C.

NMR (CDCl₃): δ (ppm) 8.95 (bs, 2H), 7.97 (s, 1H), 7.75 (s, 1H),7.22-7.08 (m, 4H), 4.58-4.41 (2d, 2H), 4.50 (dd, 1H), 3.44 (m, 1H),3.4-3.1 (m, 5H), 2.84 (s, 3H), 2.80 (m, 1H), 1.12 (d, 3H), 1.07 (d, 3H).

IR (Nujol) (cm⁻¹) 3437, 1653

MS (m/z) 488 [M−Cl]⁺

EXAMPLE 3 2-(2-Isopropyl-phenyl)-piperazine-1-carboxylic acid(3,5-bis-trifluoromethyl-benzyl)-methyl-amide hydrochloride

To a solution of intermediate 15 (0.108 g) in anh. EtOH (2.0 mL), atr.t., under N₂, Pd/C 10% (20 mg, 20% wt) was added. The black suspensionwas placed under an atmosphere of H₂ and was stirred for 3 hr. Thecatalyst was then filtered on Celite and the Celite cake was rinsed withEtOH. HCl 1.0M in Et₂O was then added (350 μL). The solvent wasevaporated and the oil obtained was triturated with Et₂O. The solid wasfiltered, rinsed with Et₂O and dried under vacuum. The title compoundwas obtained as a brown solid (29 mg).

m.p. 108-110° C.

NMR (CDCl₃): δ (ppm) 9.15 (bd, 1H), 8.92 (bd, 1H), 7.97 (s, 1H), 7.66(s, 2H), 7.30 (m, 1H), 7.27 (m, 1H), 7.19 (dt, 1H), 7.03 (dt, 1H), 4.69(dd, 1H), 4.55 (2d, 2H), 3.53 (m, 1H), 3.39 (m, 3H), 3.19 (bd, 1H), 3.04(dt, 1H), 2.92 (m, 4H), 1.24 (d, 3H), 1.20 (d, 3H).

IR (Nujol) (cm⁻¹) 3441, 1662.

MS (m/z) 489 [M−Cl]⁺.

EXAMPLE 4 2-(4-Fluoro-3-methyl-phenyl)-piperazine-1-carboxylic acid(3,5-bis-trifluoromethyl-benzyl)-methyl-amide hydrochloride

To a solution of intermediate 16 (0.226 g) in anh. EtOH (3.7 mL), atr.t., under N₂, Pd/C 10% (23 mg, 10% wt) was added. The black suspensionwas placed under an atmosphere of H₂ and stirred for 3 hr. The catalystwas then filtered on Celite and the Celite cake was rinsed with EtOH.HCl 1.0M in Et₂O was then added (740 μL). The solvent was evaporated andthe oil obtained was treated with Et₂O. The solid obtained was filtered,rinsed with Et₂O and dried under vacuum to give the title compound as awhite solid (112 mg).

m.p. 70-72° C.

NMR (CDCl₃): δ (ppm) 9.08 (m, 2H), 7.97 (s, 1H), 7.67 (s, 2H), 7.19 (m,1H), 7.14 (m, 1H), 7.01 (t, 1H), 4.59 (d, 1H), 4.43 (m, 1H), 4.40 (d,1H), 3.1-3.5 (m, 6H), 2.92 (s, 3H), 2.14 (s, 3H).

IR (Nujol) (cm⁻¹) 3406, 1653

MS (m/z) 478 [M−Cl]⁺

EXAMPLE 5 2-(2,4-Difluoro-phenyl)-piperazine-1-carboxylic acid(3,5-bis-trifluoromethyl-benzyl)-methyl-amide hydrochloride

To a solution of intermediate 17 (0.134 g) in anh. EtOH (2.0 mL), atr.t., under N₂, Pd/C 10% (27 mg, 20% wt) was added. The black suspensionwas placed under an atmosphere of H₂ and was stirred for 3 hr. Thecatalyst was then filtered on Celite and the Celite cake was rinsed withEtOH. HCl 1.0M in Et₂O was then added (436 μL). The solvent wasevaporated and the oil obtained was triturated with Et₂O. The solid wasfiltered, rinsed with Et₂O and dried under vacuum. The title compoundwas obtained as a yellow solid (112 mg).

m.p. 220-230° C.

NMR (CDCl₃): δ (ppm) 9.08-9.3 (m, 2H), 7.97 (s, 1H), 7.62 (s, 2H), 7.44(m, 1H), 7.18 (m, 1H), 6.95 (m, 1H), 4.65 (m, 1H), 4.3-4.65 (dd, 2H),3.2-3.6 (m, 4H), 3.07 (m, 2H), 2.92 (s, 3H).

IR (Nujol) (cm⁻¹) 3400, 1656

MS (m/z) 482 [M−Cl]⁺.

EXAMPLE 6 2-(4-Fluoro-2-methyl-phenyl)-piperazine-1-carboxylic acid(3,5-bis-trifluoromethyl-benzyl)-amide hydrochloride

A solution of intermediate 18 (0.086 g) in EtOH (10 ml) was hydrogenatedat atmospheric pressure for 2 hr, in the presence of 10% Pd/C (20 mg) ascatalyst. The catalyst was filtered off and the solvent was evaporated.The crude residue dissolved in Et₂O and then a 1M sol. of HCl in Et₂O(0.1 ml) was added. The solvent was evaporated to obtain the titlecompound (0.05 g) as a white solid.

NMR (DMSO) δ (ppm) 9.06 (m, 1H), 8.88 (m, 1H), 7.91 (s, 1H), 7.77 (s,2H), 7.42 (t, 1H), 7.22 (dd, 1H), 7.03 (m, 1H), 6.94 (t, 1H), 5.22 (t,1H), 4.34 (m, 2H), 3.98 (m, 1H), 3.64 (m, 1H), 3.4-3.2 (m, 2H), 3.22 (m,2H), 2.32 (s, 3H).

IR (Nujol) (cm⁻¹) 3360, 1645.

MS (m/z) 464 [M−Cl]⁺.

EXAMPLE 7 (+)-2-(R)-(4-Fluoro-2-methyl-phenyl)-piperazine-1-carboxylicacid (3,5-bis-trifluoromethyl-benzyl)-methyl-amide hydrochloride

A solution of intermediate 20a (0.120 g) in EtOH (5 mL) was hydrogenatedat atmospheric pressure for 4 hr, in the presence of 10% Pd/C (25 mg).Then the catalyst was filtered off and the solvent was evaporated. Thecrude product was dissolved in Et₂O and then a solution 1M of HCl inEt₂O (0.3 mL) was added. Then the precipitate was filtered and washedwith Et₂O to obtain the title compound (0.057 g) as a white solid.

m.p.>220° C.

NMR (DMSO) δ (ppm) 9.11 (m, 1H); 8.83 (m, 1H); 7.96 (s, 1H); 7.59 (s,2H); 7.34 (dd, 1H); 6.94 (dd, 1H); 6.86 (m, 1H); 4.65-4.35 (dd, 2H);4.49 (m, 1H); 3.54 (m, 1H); 3.44-3.01 (m, 4H); 2.93 (s, 3H); 2.90 (m,1H); 2.38 (s, 3H).

MS (m/z) 479 [MH−Cl]⁺

[α]^(D) ₂₀=+69.5 C=0.27 (g/100 ml) CHCl₃

EXAMPLE 8 (−)-2-(S)-(4-Fluoro-2-methyl-phenyl)-piperazine-1-carboxylicacid (3,5-bis-trifluoromethyl-benzyl)-methyl-amide hydrochloride MethodA

A solution of intermediate 20b (0.110 g) in EtOH (5 mL) was hydrogenatedat atmospheric pressure for 4 hr, in the presence of 10% Pd/C (25 mg).Then the catalyst was filtered off and the solvent was evaporated. Thecrude product was dissolved in Et₂O and then a solution 1M of HCl inEt₂O (0.3 mL) was added. Then the precipitate was filtered and washedwith diethyl ether to obtain the title compound (0.045 g) as a whitesolid.

Method B

A solution of intermediate 37a (0.24 g) in EtOH (4 mL) was hydrogenatedat atmospheric pressure for 3 hr, in the presence of 10% Pd/C (73 mg) ascatalyst. The catalyst was filtered off and the solvent was evaporated.The crude residue was dissolved in Et₂O and then a 1M sol. of HCl inEt₂O (0.58 mL) was added. The formed precipitate was filtered and washedwith diethyl ether to obtain the title compound (0.04 g) as a whitepowder.

Method C

To Intermediate 39 (2.37 g) TEA (3.15 mL) in dry DCM (57 mL) was addeddropwise, at 0° C. Then a solution of triphosgene (1.502 g) in dry DCM(12 mL) under inert atmosphere was added. The temperature was maintainedat 0° C. for 3 hr, before the addition of DIPEA (4 mL) followed by3,5-bis-trifluoromethylbenzyl-N-methyl amine (4.62 g) in acetonitrile(142 mL). The reaction mixture was heated to reflux for 3 hr then cooledto room temperature diluted with DCM (25 mL) and washed with a 1Nsolution of HCl (25 mL), H₂O (25 mL) and brine (25 mL) in sequence. Theorganic phase was dried and the crude product obtained after evaporationof the solvent was purified by flash chromatography (from AcOEt/CH 4:1to pure AcOEt) to give2-(4-Fluoro-2-methyl-phenyl)-3-oxo-piperazine-1-carboxylic acid(3,5-bis-trifluoromethyl-benzyl)-methyl-amide as a foam (1.79 g).

This compound was reduced with BH₃.THF (17.6 mL) following the standardprocedure (4 hr reflux in 10 ml of THF, then work-up with 6 mL of HCl37% and subsequent neutralisation with 5 g of solid NaHCO₃) to give thetitle compound (1.16 g).

m.p.>220° C.

NMR (DMSO) δ (ppm) 9.11 (m, 1H); 8.83 (m, 1H); 7.96 (s, 1H); 7.59 (s,2H); 7.34 (dd, 1H); 6.94 (dd, 1H); 6.86 (m, 1H); 4.65-4.35 (dd, 2H);4.49 (m, 1H); 3.54 (m, 1H); 3.44-3.01 (m, 4H); 2.93 (s, 3H); 2.90 (m,1H); 2.38 (s, 3H).

MS (m/z) 479 [MH−Cl]⁺

[α]^(D) ₂₀=−72.6 C=0.27 (g/100 ml) CHCl₃

EXAMPLE 9 2-(4-Fluoro-2-methyl-phenyl)-piperazine-1-carboxylic acid[1-(3,5-bis-trifluoromethyl-phenyl)ethyl]-methyl-amide hydrochloride(mixture of enantiomers A,B)

A solution of intermediate 22a (0.05 g) in EtOH (5 mL) was hydrogenatedat atmospheric pressure for 1½ hr, in the presence of 10% Pd/C (15 mg).Then the catalyst was filtered off and the solvent was evaporated. Thecrude product was dissolved in Et₂O and then a solution 1M of HCl inEt₂O (0.5 mL) was added. Then the precipitate was filtered and washedwith Et₂O to obtain the title compound (0.025 g) as a white powder.

NMR (CDCl₃) δ (ppm) 10.2 (b, 1H); 7.78 (s, 1H); 7.54 (s, 2H); 7.13 (dd,1H); 6.88 (dd, 1H); 6.82 (m, 1H); 5.48 (q, 1H); 4.57 (m, 1H); 3.6-3.5(m, 2H); 3.38 (m, 2H); 3.3-3.0 (m, 2H); 2.71 (s, 3H); 2.48 (s, 3H); 1.44(d, 3H).

IR (CDCl₃) 1663

MS (m/z) 491 [M−Cl]⁺

EXAMPLE 10 2-(4-Fluoro-2-methyl-phenyl)-piperazine-1-carboxylic acid[1-(3,5-bis-trifluoromethyl-phenyl)-ethyl]-methyl-amide hydrochloridemixture of enantiomers C,D)

A solution of intermediate 22b (0.05 g) in EtOH (5 mL) was hydrogenatedat atmospheric pressure for 1½ hr, in the presence of 10% Pd/C (15 mg).Then the catalyst was filtered off and the solvent was evaporated. Thecrude product was dissolved in Et₂O and then a solution 1M of HCl inEt₂O (0.5 mL) was added. Then the precipitate was filtered and washedwith Et₂O to the title compound (0.057 g) as a white powder.

NMR (CDCl₃) δ (ppm) 10.2 (b, 1H); 7.74 (s, 1H); 7.41 (s, 2H); 7.10 (m,1H); 6.88 (m, 1H); 6.80 (m, 1H); 5.58 (q, 1H); 4.85 (m, 1H); 3.7-2.9 (m,6H); 2.80 (s, 3H); 2.49 (s, 3H); 1.44 (d, 3H).

IR (CDCl₃) 1662

MS (m/z) 491 [M−Cl]⁺

EXAMPLE 11 2-(4-Fluoro-2-methyl-phenyl)-piperazine-1-carboxylic acid(3,5-bis-trifluoromethyl-benzyl)-methyl-amide

To a solution of intermediate 32 (813 mg) in anh. THF (6.6 mL), at r.t.,under N₂, BH₃.THF 1M in THF (9.9 mL) was added. The solution was heatedat reflux for 3 hr. It was then brought back to r.t. and 1N HCl (4 mL)was added slowly in order to destroy the borane complexes. The reactionmixture was stirred at r.t. for 18 hr. The THF was evaporated and theaqueous phase was basified with 10% NaOH. It was then extracted withEtOAc (3×). The combined organic extracts were dried, the solids werefiltered and the solvent evaporated. The title compound was used in thenext step (790 mg) without any further purification.

NMR (CDCl₃): δ (ppm) 7.77 (s, 1H), 7.49 (s, 2H), 7.33 (m, 1H), 6.86 (m,1H), 6.82 (m, 1H), 4.65-4.46 (2d (AB), 2H), 4.46 (m, 1H), 3.40-2.85 (m,6H), 2.97 (s, 3H), 2.66 (s, 3H).

IR (CDCl₃, cm⁻¹): 1653.

MS (m/z): 478 [MH]⁺

EXAMPLE 12 2-(4-Fluoro-phenyl)-piperazine-1-carboxylic acid(3,4-bis-trifluoromethyl-benzyl)-methyl-amide hydrochloride

A 1M solution of BH₃.in THF (1.88 mL) was added very carefully to asolution of intermediate 33 (0.180 g) in dry THF (8 mL) under inertatmosphere; and the reaction mixture was refluxed 3 hr. After completionof the reduction, HCl 37% was added (3 mL) and the reaction mixture wasrefluxed 2 hr. THF was removed under reduced pressure, water was added(3 mL) and the aqueous solution was basified using Na₂CO₃; next, it wasextracted with DCM, washed with brine and dried. The crude product waspurified by flash chromatography (AcOEt/MeOH 8:2) affording the freeamine which was treated with a 1M solution of HCl in Et₂O (0.3 mL) toyield the title compound (0.05 g) as a white solid.

mp>200° C.

NMR (DMSO) δ (ppm): 9.08 (bs, 2H), 7.97 (s, 1H), 7.66 (s, 2H), 7.35 (m,2H), 7.10 (m, 2H), 4.60 (d, 1H), 4.46 (dd, 1H), 4.39 (d, 1H), 3.50-3.10(m, 6H), 2.92 (s, 3H).

IR (Nujol) (cm⁻¹) 3437, 1653

MS: 464 [M−Cl]⁺.

EXAMPLE 13 2-Phenyl-piperazine-1-carboxylic acid(3,5-bis-trifluoromethyl-benzyl)-methyl-amide hydrochloride

To a stirred solution of intermediate 34 (0.382 g) in THF (10 mL) a 1Msolution of BH₃ in THF (1.66 mL) was added. The mixture was thenrefluxed for 3 hr. The temperature was then cooled, and the reaction wasquenched with a solution of HCl 37% (5 mL) and stirred at roomtemperature overnight. The solution was then basified with NaOH and theproduct was extracted with DCM, dried and concentrated under reducedpressure to give an oil. The oil was then dissolved in Et₂O and a 1Msolution of HCl in Et₂O (1.6 mL) was added. After a few minutes thesolution was concentrated, and the product was triturated from petroleumether to give the title compound (0.300 g) as a solid.

NMR (CDCl₃): δ (ppm): 10.15 (b, 2H); 7.75 (s, 1H); 7.44 (s, 2H); 7.3 (m,5H); 4.80-4.34 (m, 3H); 3.80-3.00 (m, 6H); 2.93 (s, 3H)

MS (m/z):446 [M−Cl]⁺.

EXAMPLE 14 2-(2,4-Dichloro-phenyl)-piperazine-1-carboxylic acid(3,5-bistrifluoro methyl-benzyl)-methyl-amide hydrochloride

To a solution of intermediate 35 (0.22 g) in THF (15 mL) a 1M solutionof borane in THF (1.2 mL) was added and the reaction mixture was stirredat reflux for 3 hr, then cooled to r.t. 37% HCl (3 mL) was addeddrop-wise and the reaction mixture stirred for 3 hr. The solvent wasevaporated and the crude residue was diluted with AcOEt and washed witha saturated solution of NaHCO₃ and brine. The organic phase was driedand concentrated to give the crude product. The latter was dissolved inEt₂O (2 ml), then a 1M sol of HCl in Et₂O (1 mL) was added. The obtainedsolution was added dropwise in petroleum (30 mL) and the formedprecipitate was filtered to obtain the title compound (0.06 g, whitesolid).

NMR (DMSO) δ (ppm) 9.25, 9.15 (m+m, 2H), 7.98 (m, 1H), 7.64 (s, 2H),7.60 (d, 1H), 7.45 (d, 1H), 7.29 (dd, 1H), 4.78 (dd, 1H), 4.63 (d, 1H),4.35 (d, 1H), 3.59 (d, 1H), 3.40-3.25 (m, 3H), 3.07 (t, 3H), 2.95, 2.93(s+m, 4H).

IR (Nujol) (cm⁻¹) 3442, 1654

MS (m/z) 515 [M−Cl]⁺.

EXAMPLE 15 2-(3,4-Dichloro-phenyl)-piperazine-1-carboxylic acid(3,5-bistrifluoro methyl-benzyl)-methyl-amide hydrochloride

To a solution of intermediate 36 (0.13 g) in THF (20 mL) a 1M solutionof borane in THF (1.96 mL) was added and the reaction mixture wasstirred at reflux for 3 hr, then cooled to r.t. 37% HCl (5 mL) was addeddrop-wise and the reaction mixture was stirred for 3 hr. The solvent wasevaporated and the crude residue was diluted with AcOEt and washed witha saturated solution of NaHCO₃ and brine. The organic phase was driedand concentrated to give the crude product. The latter was dissolved inEt₂O (2 mL), then a 1M sol of HCl in diethyl ether (1 mL) was added. Theobtained solution was added drop-wise in petroleum (30 mL) and theformed precipitate was filtered to obtain the title compound (0.016 g,white solid).

NMR (DMSO) δ (ppm) 8.99 (broad, 2H), 7.98 (s, 1H), 7.70 (s, 2H), 7.56(d+d, 2H), 7.31 (dd, 1H), 4.58 (d, 1H), 4.50 (d, 1H), 4.41 (d, 1H),3.5-3.1 (m, 4H), 2.93 (s, 3H).

IR (Nujol) (cm⁻¹) 3436, 1653

MS (m/z) 515 [M−Cl]⁺.

EXAMPLE 16 (−)-2-(S)-(4-Fluoro-2-methyl-phenyl)-piperazine-1-carboxylicacid [1-(S)-(3,5-bis-trifluoromethyl-phenyl)-ethyl]-methyl-amidehydrochloride

A solution of intermediate 38a (0.08 g) in EtOH (5 mL) was hydrogenatedat atmospheric pressure for 4 hr, in presence of 10% Pd/C (50 mg). Thecatalyst was filtered off and the solvent was evaporated. The crudeproduct was dissolved in Et₂O and then a solution 1M of HCl in Et₂O (0.5mL) was added. The precipitate was filtered and washed with Et₂O toobtain the title compound (0.023 g).

NMR (CDCl₃) δ (ppm) 10.5-10.0 (b, 2H); 7.74 (s, 1H); 7.41 (s, 2H); 7.09(m, 1H); 6.88 (m, 1H); 6.80 (m, 1H); 5.58 (q, 1H); 4.85 (m, 1H);3.80-3.00 (m, 6H); 2.80 (s, 3H); 2.49 (s, 3H); 1.53 (d, 3H).

MS (m/z) 492

[α]^(D) ₂₀=−164.9, 0.12 (g/100 ml) CHCl₃

EXAMPLE 17 (+)-2-(R)-(4-Fluoro-2-methyl-phenyl)-piperazine-1-carboxylicacid [1-(R)-(3,5-bis-trifluoromethyl-phenyl)ethyl]-methyl-amidehydrochloride

A solution of intermediate 38 b (0.08 g) in EtOH (5 mL) was hydrogenatedat atmospheric pressure for 4 hr, in presence of 10% Pd/C (50 mg). Thecatalyst was filtered off and the solvent was evaporated. The crudeproduct was dissolved in Et₂O and then a solution 1M of HCl in Et₂O (0.5mL) was added. The precipitate was filtered and washed with Et₂O toobtain the title compound (0.020 g).

NMR (CDCl₃) δ (ppm) 10.5-10.0 (b, 2H); 7.74 (s, 1H); 7.41 (s, 2H); 7.09(m, 1H); 6.88 (m, 1H); 6.80 (m, 1H); 5.58 (q, 1H); 4.85 (m, 1H);3.80-3.00 (m, 6H); 2.80 (s, 3H); 2.49 (s, 3H); 1.53 (d, 3H).

MS (m/z) 492

[α]^(D) ₂₀=+207, 0.11 (g/100 ml) CHCl₃

EXAMPLE 18 2-(S)-(4-Fluoro-2-methyl-phenyl)-piperazine-1-carboxylic acid[1-(R)-(3,5-bis-trifluoromethyl-phenyl)-ethyl]-methyl-amide acetate salt

To a solution of intermediate 40a (8.8 g) in dry THF (33 mL) under N₂BH₃.THF (1M solution in THF-87 mL) was added and the reaction mixturewas stirred at reflux for 3 hr, then cooled to r.t. and HCl (37%, 30 mL)was added drop-wise maintaining the reaction mixture in an ice-bath. Thereaction mixture was stirred at r.t. for 1 hr. Water was then added (70mL) and solid NaHCO₃ (35.2 g) was added portion-wise until a pH of 6.5.The THF was evaporated and the aqueous phase was extracted with Et₂O(3×88 mL). The combined organic phases were dried, and evaporated toleave a colourless oil (7.37 g).

This crude oil was purified by flash chromatography (AcOEt/MeOH 7:3).The product obtained was suspended in Et₂O (125 mL) and washed withNaHCO₃ sat. (2×20 mL). The clear combined organic phases were dried andevaporated to obtain the2-(S)-(4-Fluoro-2-methyl-phenyl)-piperazine-1-carboxylic acid[1-(R)-(3,5-bis-trifluoromethyl-phenyl)-ethyl]-methyl-amide as whitefoam (5.27 g). This material (5.27 g) was dissolved in Et₂O (79 mL) andacetic acid (613 μL) was added drop-wise. The mixture was stirred atr.t. for 1 h and then at 0° C. for 1 h. The suspension was filtered togive the title compound (4.366 g) as a white solid.

NMR (1H, DMSO-d₆): δ (ppm) 7.98 (s, 1H), 7.70 (s, 2H), 7.87 (m, 1H),6.91 (m, 1H), 6.77 (m, 1H), 5.29 (q, 1H), 4.23 (dd, 1H), 3.2-2.6 (m,6H), 2.68 (s, 3H), 2.3 (s, 3H), 1.89 (s, 3H), 1.48 (d, 3H).

MS (m/z): 492 [M−CH₃COO]⁺.

[α]_(D)=−120.4° C. Solvent (CHCl3); Source: Na; Cell volume [mL]: 1;Cell pathlength [dm]: 1; Cell temperature [° C.]: 20; Wavelength [nm]:589

EXAMPLE 19 2-(S)-(4-Fluoro-2-methyl-phenyl)-piperazine-1-carboxylic acid[1-(S)-(3,5-bis-trifluoromethyl-phenyl)-ethyl]-methyl-amide acetate

To a solution of intermediate 40b (2.57 g) in dry THF (15.5 mL), at 0°C., under N₂, was added BH₃.THF (1M solution in THF) then heated atreflux for 3 hr. It was then brought back to r.t. and HCl 37% (9 mL) wasadded slowly maintaining the reaction mixture in an ice-bath. Thereaction mixture was stirred at r.t. for 1 hr. Water was then added(20.5 mL) and solid NaHCO₃ (10.3 g) was added portion-wise until a pH of7.

The THF was evaporated and the aqueous phase was extracted with Et₂O(3×25.7 mL). The combined organic phases were dried and evaporated toleave a yellow oil (2.34 g). This crude oil was dissolved in Et₂O (35mL) and glacial AcOH (0.245 mL) was added drop-wise. The mixture wasstirred 2 hr at 0° C., then it was filtered, washed with Et₂O (10 mL)and dried under vacuum to obtain the title compound as a white solid(1.349 gr).

NMR (1H, DMSO-d₆): δ (ppm) 7.92 (s, 1H), 7.58 (s, 1H), 7.29 (m, 1H),6.90 (m, 1H), 6.77 (m, 1H), 5.33 (q, 1H), 4.19 (m, 1H), 3.2-2.6 (m, 6H),2.79 (s, 3H), 2.32 (s, 3H), 1.89 (s, 3H), 1.48 (d, 3H).

MS (m/z): 492 [M−CH₃COO]⁺.

[α]_(D)=+2.2° C.

Solvent (CHCl₃); Source: Na; Cell volume [mL]: 1; Cell pathlength [dm]:1;

Cell temperature [° C.]: 20; Wavelength [nm]: 589

EXAMPLE 204-(2-Amino-acetyl)-2-(S)-(4-fluoro-2-methyl-phenyl)-piperazine-1-carboxylicacid (3,5-bis-trifluoromethyl-benzyl)-methyl-amide hydrochloride

Example 8 (0.05 g) was dissolved in dry DMF (2 mL), DIPEA (0.019 mL) wasadded and the solution thus obtained was added to a solution ofN-(tert-butoxycarbonyl)glycine (0.0192 g),1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (0.0214 g) and1-hydroxybenzotriazole (0.015 g) in dry DMF (5 mL). The reaction mixturewas stirred 18 hr at room temperature, then diluted with AcOEt (30 mL),washed with water (30 mL), sodium bicarbonate (30 mL) and brine (30 mL).The separated organic layer was dried and evaporated to give a crude,which was purified by flash chromatography (AcOEt). The compoundobtained (0.043 g) was dissolved in a 1M solution of HCl in Et₂O (5 mL),stirred 0.5 hr at room temperature and evaporated to obtain the titlecompound (0.046 g) as a yellow foam.

NMR (DMSO) δ (ppm) 8.01 (bs, 3H), 7.88 (s, 1H), 7.67 (s, 2H), 7.33 (m,1H), 6.95 (m, 1H), 6.83 (m, 1H), 4.60 (m, 1H), 4.60-4.42 (dd, 2H),4.2-3.3 (m, 6H), 3.2 (m, 2H), 2.89 (s, 3H), 2.4 (s, 3H).

IR (Nujol) (cm⁻¹) 3410, 1660.

MS (m/z) 535 [M−Cl]⁺.

EXAMPLE 21 2-(S)-(4-Fluoro-2-methyl-phenyl)-piperazine-1-carboxylic acid[1-(3,5-bis-trifluoromethyl-phenyl)-1-methyl-ethyl]-methyl-amidehydrochloride

Palladium on charcoal (10%-17.5 mg) was added to a solution ofintermediate 73 (145 mg) in ethanol (2 mL). The resulting mixture wasstirred at 1 atm and r.t. under hydrogen atmosphere for 2 hrs. Themixture was filtered and concentrated in vacuo. The residue wasdissolved in Et₂O (2 mL) and treated with HCl 1M in Et₂O (1 mL). themixture was stirred at r.t. for 10 min, then concentrated in vacuo andthe residue triturated with Et₂O/petroleum to give the title compound(27 mg) as white solid.

NMR (d₆-DMSO): δ (ppm) 9.15 (bs, 1H); 8.9 (bs, 1H); 7.77 (s, 1H); 7.71(s, 2H); 7.31 (dd, 1H); 6.95-6.87 (m, 2H); 4.39 (dd, 1H); 3.71 (dt, 1H);3.35-2.9 (m, 5H); 3.24 (s, 3H); 2.23 (s, 3H); 1.49 (s, 3H); 1.46 (s,3H).

MS: m/z=506 [MH]⁺.

EXAMPLE 224-(2-Amino-ethyl)-2-(S)-(4-fluoro-2-methyl-phenyl)-piperazine-1-carboxylicacid (3,5-bis-trifluoromethyl-benzyl)-methyl-amide dihydrochloride salt

To a solution of intermediate 41 (25 mg) in absolute EtOH (1 mL), atroom temperature, was added methylamine 8.03M in EtOH (48 μL). Thereaction mixture was stirred at r.t. for 5 hr. The solvent wasevaporated and the crude product purified by flash chromatography(AcOEt/MeOH/NH₄OH conc. 90:5:5). The fractions were collected and thesolvent was evaporated. The residue was dissolved in Et₂O and HCl 1.0Min Et₂O (150 μL) was added. The yellow precipitate was filtered anddried to give the title compound (19 mg) as a yellow solid.

NMR (DMSO) δ (ppm) 8.12 (bs, 2H), 7.90 (s, 1H), 7.62 (s, 2H), 7.33 (t,1H), 6.95 (dd, 1H), 6.83 (td, 1H), 4.69 (m, 1H), 4.62 (d, 1H), 4.41 (d,1H), 3.60-3.10 (m, 10H), 2.94 (s, 3H), 2.40 (s, 3H).

IR (Nujol) (cm⁻¹) 3433-3300, 1651.

MS (m/z) 521 [M−2HCl+H]⁺.

EXAMPLE 23 2-(4-Fluoro-2-methyl-phenyl)-3-methyl-piperazine-1-carboxylicacid (3,5-bis-trifluoromethyl-benzyl)-methyl-amide hydrochloride salt

To a solution of intermediate 45 (100 mg) in anh. MeOH (3 mL), under N₂,at room temperature, was added Pd/C 10% (20 mg). The reaction mixturewas placed under an H₂ atmosphere and stirred at room temperature for 2hr. The catalyst was filtered on Celite, and the Celite cake was rinsedwith AcOEt. The solvent was evaporated and the residue was dissolved inEt₂O. HCl 1.0N in Et₂O (240 μl) was added and the white precipitate wasfiltered and rinsed with Et₂O. The title compound was obtained (73 mg)as a white solid.

NMR (CDCl₃) δ (ppm) 9.31+9.01 (m, 2H), 7.99 (s, 1H), 7.70 (s, 2H), 7.02(m, 2H), 6.78 (m, 1H), 4.63 (d, 1H), 4.7-4.3 (dd, 2H), 3.66 (m, 1H),3.5-2.9 (m, 4H), 3.05 (s, 3H), 2.34 (s, 3H), 1.09 (d, 3H).

IR (Film) (cm⁻¹) 1659.

MS (m/z) 692 [MH−Cl]⁺.

EXAMPLE 24 2-(2-Methyl-4-fluoro-phenyl)-6-methyl-piperazine-1-carboxylicacid (3,5-bis-trifluoromethyl-benzyl)-methyl-amide hydrochloride salt

BH₃.THF complex (1.25 mL) was added very carefully to a solution ofintermediate 47 (0.080 g) in dry THF (5 mL) under inert atmosphere andthe reaction mixture was refluxed for 3 hr. After completion of thereduction, HCl 37% was added (3 mL) and the reaction mixture wasrefluxed for 2 hr. THF was removed under reduced pressure, water wasadded (3 mL) and the aqueous solution was basified by means of Na₂CO₃,extracted with DCM, washed with brine and dried. The crude product waspurified by flash chromatography (AcOEt/MeOH 8:2) to afford a productwhich was dissolved in Et₂O and treated with HCl 1.0M in Et₂O (0.3 mL)to give the title compound (0.03 mg).

¹H-NMR (DMSO) δ (ppm) 9.12 (bs, 1H), 8.88 (bs, 1H), 7.93 (s, 1H), 7.56(s, 2H), 7.37 (m, 1H), 6.74 (m, 2H), 4.71 (d, 1H), 4.35 (dd, 1H),4.36-4.10 (bm, 1H), 3.35-2.9 (m, 5H), 2.99 (s, 3H), 2.28 (s, 3H), 1.05(d, 3H).

MS (m/z) 492 [M−Cl]⁺.

mp>200° C.

EXAMPLE 25 2-(S)-(4-Fluoro-2-methyl-phenyl)-piperazine-1-carboxylic acid[(1-3,5-bis-trifluoromethyl-phenyl)-cyclopropyl]-methyl-amidehydrochloride

Conc. HCl (0.27 mL) was added to a solution of intermediate 53 (90 mg)in methanol (9 mL) and the mixture was refluxed for 15 min. The mixturewas concentrated in vacuo and the residue triturated with Et₂O to givethe title compound (32 mg) as white solid.

IR (nujol): 3405 (NH₂ ⁺), 1653 (C═O) cm⁻¹.

NMR (DMSO) δ (ppm) 9.42 (bs, 1H); 9.27 (bs, 1H); 7.79 (bs, 1H), 7.45(dd, 1H); 7.25 (bs, 2H); 6.94 (m, 2H), 4.52 (dd, 1H), 3.5-3.06 (m, 9H);2.33 (s, 3H), 1.34 (m, 2H); 1.22 (m, 2H).

MS: m/z=504 [M−Cl]⁺.

EXAMPLE 26[2-(3,5-Bis-trifluoromethyl-phenyl)-pyrrolidin-1-yl]-[2-(S)-(4-fluoro-2-methyl-phenyl)-piperazin-1-yl]-methanonehydrochloride (enantiomer A)

Conc. HCl (0.3 mL) was added to a solution of intermediate 58a (15 mg)in methanol (5 mL) and the mixture was refluxed for 2 hrs. The mixturewas concentrated in vacuo to give the title compound (7 mg) as whitesolid.

IR (nujol) 1654 (C═O) cm⁻¹.

NMR (DMSO) δ (ppm) 9.17 (bs, 1H); 8.88 (bs, 1H); 7.93 (s, 1H), 7.86 (s,2H); 7.23 (m, 1H); 6.94 (m, 2H), 4.78 (t, 1H), 4.46 (dd, 1H); 3.88-3.83(m, 2H); 3.79 (m, 1H); 3.4 (m, 1H); 3.28 (m, 1H); 3.2 (d, 1H); 3.06 (t,1H); 2.84 (m, 1H); 2.31 (m, 1H), 2.27 (s, 3H); 1.96 (m, 1H); 1.74 (m,1H); 1.62 (m, 1H).

MS: m/z=504 [MH−HCl]⁺.

EXAMPLE 27[2-(3,5-Bis-trifluoromethyl-phenyl)-pyrrolidin-1-yl]-[2-(S)-(4-fluoro-2-methyl-phenyl)-piperazin-1-yl]-methanonehydrochloride (enantiomer B)

Conc. HCl (0.3 mL) was added to a solution of intermediate 58b (20 mg)in methanol (5 mL) and the mixture was refluxed for 2 hrs. The mixturewas concentrated in vacuo to give the title compound (11 mg) as whitesolid.

IR (nujol) 1659 (C═O) cm⁻¹.

NMR (DMSO) δ (ppm) 9.09 (bm, 1H); 8.89 (bm, 1H); 7.83 (s, 1H), 7.52 (s,2H); 7.45 (dd, 1H); 6.97 (td, 1H), 6.9 (dd, 1H); 4.93 (dd, 1H), 4.39(dd, 1H); 3.88-3.22 (m, 6H); 3.07 (t, 1H); 2.99 (m, 1H); 2.3 (m, 1H),2.25 (s, 3H); 1.80 (m, 1H); 1.75 (m, 1H); 1.63 (m, 1H).

MS: m/z=504 [MH−HCl]⁺.

EXAMPLE 28[2-(3,5-Bis-trifluoromethyl-phenyl)-3,6-dihydro-2H-pyridyn-1-yl]-[2-(S)-(4-fluoro-2-methyl-phenyl)-piperazin-1-yl]-methanonehydrochloride (enantiomer A)

Trifluoroacetic acid (5 mL) was added to a solution of intermediate 62(172 mg) in DCM (5 mL) and the resulting solution was stirred at r.t.for 30 minutes. The mixture was concentrated in vacuo, then partitionedbetween 10% potassium carbonate solution and AcOEt. The organic layerwas dried and concentrated in vacuo: the residue was dissolved in Et₂Oand treated with HCl 1M in Et₂O (5 mL) the mixture was stirred at r.t.for 30 min, then concentrated in vacuo and the residue triturated withEt₂O to give the title compound (90 mg) as white solid.

IR (nujol) 1656 (C═O) cm⁻¹.

NMR (DMSO) δ (ppm) 9.4-9.2 (bs, 2H); 7.95 (s, 1H); 7.54 (s, 2H); 7.32(dd, 1H); 6.98 (dd, 1H), 6.85 (dt, 1H); 5.9 (bm, 1H); 5.72 (m, 1H); 5.47(d, 1H); 4.57 (dd, 1H); 4.41 (bd, 1H); 3.4-3.25 (m, 5H); 3.14 (t, 1H);2.91 (t, 1H); 2.72 (dd, 1H); 2.55 (m, 1H), 2.37 (s, 3H).

EXAMPLE 29[2-(3,5-Bis-trifluoromethyl-phenyl)-piperidin-1-yl]-[2-(S)-(4-fluoro-2-methyl-phenyl)-piperazin-1-yl]-methanonehydrochloride (enantiomer A)

Palladium on charcoal (10%-14 mg) was added to a solution ofintermediate 62 (145 mg) in AcOEt (5 mL). The resulting mixture wasstirred at 1 atm and r.t. under hydrogen atmosphere for 3 hrs. Themixture was filtered and concentrated in vacuo. DCM (5 mL) andtrifluoroacetic acid (5 mL) were added to the residue and the resultingsolution was stirred at r.t. for 30 minutes. The mixture wasconcentrated in vacuo, then partitioned between 10% potassium carbonatesolution and AcOEt. The organic layer was dried and concentrated invacuo: the residue was dissolved in Et₂O and treated with HCl 1M in Et₂O(5 mL). the mixture was stirred at r.t. for 15 min, then concentrated invacuo and the residue triturated with Et₂O to give the title compound(42 mg) as white solid.

IR (nujol) 3200-2500 (NH₂ ⁺), 1656 (C═O) cm⁻¹.

NMR (DMSO) δ (ppm) 9.4 (bs, 2H); 7.92 (bs, 1H); 7.48 (bs, 2H); 7.43 (dd,1H); 6.97 (dd, 1H), 6.93 (m, 1H); 5.25 (bm, 1H); 4.61 (dd, 1H); 4.15(bd, 1H); 3.5-3.2 (bm, 5H); 2.92 (t, 1H); 2.79 (m, 1H); 2.36-2.42 (m,4H); 1.78-1.58 (m, 4H); 1.17 (m, 1H).

EXAMPLE 30 2-(4-Fluoro-2-methyl-phenyl)-piperazine-1-carboxylic acid[1-(3,5-bis-trifluoromethyl-phenyl)-but-3-enyl]-methyl-amidehydrochloride (diastereoisomer A)

DCM (2 mL) and trifluoroacetic acid (5 mL) were added to intermediate 65(44 mg) and the resulting solution was stirred at r.t. for 30 minutes.The mixture was concentrated in vacuo, then partitioned between 10%sodium carbonate solution and AcOEt. The organic layer was dried andconcentrated in vacuo: the residue was dissolved in Et₂O and treatedwith HCl 1M in Et₂O (5 mL). The mixture was stirred at r.t. for 10 min,then concentrated in vacuo to give the title compound (43 mg) as whitesolid.

NMR (DMSO) δ (ppm) 9.05 (bs, 1H); 8.81 (bs, 1H); 7.96 (bs, 1H); 7.55(bs, 2H); 7.25 (dd, 1H); 6.97 (dd, 1H), 6.78 (dt, 1H); 5.7 (m, 1H); 5.35(dd, 1H); 5.22-5.06 (2m, 2H), 4.47 (dd, 1H); 3.5-2.37 (m, 15H).

EXAMPLE 31 2-(4-Fluoro-2-methyl-phenyl)-piperazine-1-carboxylic acid[1-(3,5-bis-trifluoromethyl-phenyl)-but-3-enyl]-methyl-amidehydrochloride (diastereoisomer B)

DCM (2 mL) and trifluoroacetic acid (5 mL) were added to intermediate 66(44 mg) and the resulting solution was stirred at r.t. for 30 minutes.The mixture was concentrated in vacuo, then partitioned between 10%sodium carbonate solution and AcOEt. The organic layer was dried andconcentrated in vacuo: the residue was dissolved in Et₂O and treatedwith HCl 1M in Et₂O (5 mL). The mixture was stirred at r.t. for 10 min,then concentrated in vacuo to give the title compound (39 mg) as whitesolid.

IR (nujol): 3422 (NH₂ ⁺), 1726 (C═O) cm⁻¹

NMR (DMSO) δ (ppm) 9.24 (bm, 1H); 9.02 (bm, 1H); 7.99 (s, 1H); 7.78 (s,2H); 7.26 (dd, 1H); 6.97 (dd, 1H), 6.87 (dt, 1H); 5.47 (m, 1H); 5.2 (t,1H); 5.03 (dd, 1H); 4.89 (d, 1H); 4.49 (dd, 1H); 3.36 (m, 2H); 3.24 (m,2H); 2.97 (m, 2H); 2.85 (s, 3H); 2.74 (t, 2H), 2.37 (s, 3H).

EXAMPLE 32 2-(4-Fluoro-2-methyl-phenyl)-piperazine-1-carboxylic acid[1-(3,5-bis-trifluoromethyl-phenyl)-2-methyl-propyl]-methyl-amidehydrochloride (diastereoisomer A)

Trifluoroacetic acid (1 mL) was added to a solution of intermediate 77a(35 mg) in DCM (1.5 mL) and the resulting solution was stirred at r.t.for 30 minutes. The mixture was concentrated in vacuo, then partitionedbetween 10% potassium carbonate solution and AcOEt. The organic layerwas dried and concentrated in vacuo: the residue was dissolved in Et₂Oand treated with HCl 1M in Et₂O (1 mL). The mixture was stirred at r.t.for 10 min, then concentrated in vacuo and the residue triturated withEt₂O to give the title compound (20 mg) as white solid.

NMR (d₆-DMSO): δ (ppm) 8.87 (bs, 2H); 8.02 (s, 1H); 7.88 (s, 1H); 7.26(m, 1H); 6.96 (m, 1H); 6.86 (m, 1H); 4.71 (bm, 1H); 4.42 (dd, 1H);3.4-3.0 (m, 4H); 2.88-2.79 (m, 5H); 2.63-2.38 (m, 4H); 0.62 (d, 3H);0.58 (d, 3H).

MS: m/z=520 [M−Cl]⁺.

EXAMPLE 33 2-(4-Fluoro-2-methyl-phenyl)-piperazine-1-carboxylic acid[1-(3,5-bis-trifluoromethyl-phenyl)-2-methyl-propyl]-methyl-amidehydrochloride (diastereoisomer B)

Trifluoroacetic acid (1 mL) was added to a solution of intermediate 77b(37 mg) in DCM (1.5 mL) and the resulting solution was stirred at r.t.for 30 minutes. The mixture was concentrated in vacuo, then partitionedbetween 10% potassium carbonate solution and AcOEt. The organic layerwas dried and concentrated in vacuo: the residue was dissolved in Et₂Oand treated with HCl 1M in Et₂O (1 mL). The mixture was stirred at r.t.for 10 min, then concentrated in vacuo and the residue triturated withEt₂O to give the title compound (20 mg) as white solid.

NMR (d₆-DMSO): δ (ppm) 9.14-8.89 (bs, 2H); 7.96 (s, 1H); 7.69 (s, 2H);7.02-6.95 (dd, 2H); 6.58 (m, 1H); 4.71 (d, 1H); 4.45 (dd, 1H); 3.5-3.2(m, 4H); 2.95-2.80 (m, 5H); 2.6-2.38 (m, 4H); 0.87 (d, 3H); 0.72 (d,3H).

MS: m/z=520 [M−Cl]⁺.

EXAMPLE 34 2-(4-Fluoro-2-methyl-phenyl)-piperazine-1-carboxylic acid[(3,5-bis-trifluoromethyl-phenyl)-cyclopropyl-methyl]-methyl-amidehydrochloride (diastereoisomer A)

Conc. HCl (50 μL) was added to a solution of intermediate 80 (10 mg) inmethanol (1 mL) and the mixture was refluxed for 15 min. The mixture wasconcentrated in vacuo and the residue triturated with Et₂O to give thetitle compound (4 mg) as white solid.

NMR (DMSO) δ (ppm) 9.33 (bm, 1H); 9.16 (m, 1H); 8.0 (bs, 1H), 7.79 (bs,2H); 7.3 (dd, 1H); 6.95 (m, 2H), 4.48 (dd, 1H), 4.27 (d, 1H); 3.5-2.8(m, 9H); 2.34 (s, 3H), 1.47 (m, 1H); 0.64 (m, 1H); 0.45 (m, 1H); 0.38(m, 1H); 0.08 (m, 1H).

EXAMPLE 35[2-(3,5-Bis-trifluoromethyl-phenyl)-3,6-dihydro-2H-pyridyn-1-yl]-[2-(4-fluoro-2-methyl-phenyl)-piperazin-1-yl]-methanonehydrochloride (diastereoisomer A)

Trifluoroacetic acid (5 mL) was added to a solution of intermediate 68(172 mg) in DCM (5 mL) and the resulting solution was stirred at r.t.for 30 minutes. The mixture was concentrated in vacuo, then partitionedbetween 10% potassium carbonate solution and AcOEt. The organic layerwas dried and concentrated in vacuo: the residue was dissolved in Et₂Oand treated with HCl 1M in Et₂O (5 mL). The mixture was stirred at r.t.for 30 min, then concentrated in vacuo and the residue triturated withEt₂O to give the title compound (90 mg) as white solid.

IR (nujol) 1656 (C═O) cm⁻¹.

NMR (DMSO) δ (ppm) 9.23 (bs, 1H); 9.17 (bs, 2H); 7.89 (s, 1H); 7.56 (s,2H); 7.32 (dd, 1H); 6.95 (dd, 1H), 6.82 (dt, 1H); 5.9 (m, 1H); 5.72 (d,1H); 5.47 (d, 1H); 4.6 (dd, 1H); 4.4 (m, 1H); 3.4-3.2 (m, 6H); 2.94 (m,1H); 2.7 (dd, 1H); 2.56 (m, 1H), 2.36 (s, 3H).

EXAMPLE 36 2-(S)-(4-Fluoro-2-methyl-phenyl)-piperazine-1-carboxylic acid[1-(R)-(3,5-bis-trifluoromethyl-phenyl)-ethyl]-methyl-amidemethansulphonate

To a suspension of intermediate 81 (4.9 Kg) in AcOEt (137.2 L),triethylamine (5.63 L) was added. The mixture was cooled to 0° C. then asolution of diterbuthyl dicarbonate (3.134 Kg) in AcOEt (24.5 L) wasadded in 35 min, maintaining the temperature between 0 and 5° C. Thesuspension was stirred at 0° C. for 15 min, at 20/25° C. for 1 hr, thenwashed with water (3×39.2 L), concentrated to 24.5 L and then added to asolution of triphosgene (1.97 Kg) in AcOEt (24.5 L) cooled to 0° C.Triethylamine (3.28 L) was then added in 40 min, maintaining thetemperature between 0 and 8° C. The suspension was stirred for 1 h and45 min at 20/25° C. and 30 min at 70 C and then the solution ofintermediate 82 diluted with AcOEt (49 L) and triethylamine (2.6 L) wasadded in 30 min. The mixture was refluxed for 15 hrs.

The reaction mixture, cooled at 20/25° C. was treated with aqueoussolution of NaOH 10% v/v (36.75 L). Organic phase was washed with HCl 4%v/v (46.55 L) and NaCl 11.5% p/p (4×24.5 L) then concentrated to 14.7 L.and diluted with Ciclohexane (39.2 L). The mixture was filtered througha silica pad (4.9 Kg) that was washed twice with a mixture of CH/AcOEt85/15 (2×49 L). To the Eluted phases (14.7 L) cooled at 20/25° C.,methyl tertbutyl ether (49 L) and methansulphonic acid (4.067 L) wereadded. The mixture was washed with NaOH 10% v/v (31.85 L) then withwater (4×31.85 L). Organic phase was concentrated to 9.8 L, methyltertbutyl ether (49 L) was added and the solution filtered through a 5micron filter then concentrated to 9.8 L. At 20/25° C. MTBE (29.4 L) andmetansulphonic acid (1.098 L) were added. The suspension was refluxedfor 10 min, stirred at 20/25° C. for 10 hrs and 2 hrs at 0° C. Then theprecipitate was filtered, washed with methyl tertbutyl ether (4.9 L)dried under vacuum at 20/25° C. for 24 hrs to obtain the title compound(5.519 Kg.) as white solid.

¹H-NMR (DMSO) δ (ppm) 8.99 (bm, 1H); 8.66 (bm, 1H); 8.00 (bs, 1H); 7.69(bs, 2H); 7.27 (dd, 1H); 7.00 (dd, 1H); 6.83 (m, 1H); 5.32 (q, 1H); 4.47(dd, 1H); 3.50-3.20 (m, 4H); 2.96 (m, 2H); 2.72 (s, 3H); 2.37 (s, 3H);2.28 (s, 3H); 1.46 (d, 3H).

ES⁺: m/z 492 [MH−CH₃SO₃H]⁺

ES⁻: m/z 586 [M−H]⁻; 95 [CH₃SO₃]⁻

EXAMPLE 37 2-(S)-(4-Fluoro-2-methyl-phenyl)-piperazine-1-carboxylic acid[1-(R)-(3,5-bis-trifluoromethyl-phenyl)-ethyl]-methyl-amide

To a solution of intermediate 40a (15.6 g) in anhydrous THF (94 ml), at0° C., under N₂, BH₃THF 1M/THF (154 ml) was added. The solution washeated at reflux for 3 hr. HCl 37% (54 ml) was slowly added maintainingthe reaction mixture in an ice-bath and the reaction mixture was stirredat rt for 1 hr. Water was then added (125 ml) and solid NaHCO₃ (62.4 g)was added portionwise until a pH of 6.5. The aqueous phase was extractedwith Et₂O (4×160 ml) and the combined organic extracts were dried overNa₂SO₄, the solids were filtered and evaporated to leave a colourlessoil which was purified by flash chromatography (silica gel,EtOAc/Methanol 7/3). The obtained product was suspended in Et₂O (220 ml)and washed with NaHCO₃ sat. (2×36 ml). The combined organic phases weredried (Na₂SO₄) and evaporated to give the title compound as white foam(8.7 g,).

¹H-NMR (CDCl₃) δ (ppm) 7.78 (s, 1H); 7.60 (s, 2H); 7.28 (m, 1H); 6.85(dd, 1H); 6.79 (td, 1H); 5.53 (q, 1H); 4.43 (dd, 1H); 2.9-3.5 (m, 5H);2.78 (m, 1H), 2.71 (s, 3H); 2.43 (s, 3H); 1.47 (d, 3H).

EXAMPLE 38 2-(S)-(4-Fluoro-2-methyl-phenyl)-piperazine-1-carboxylic acid[1-(R)-(3,5-bis-trifluoromethyl-phenyl)-ethyl]-methyl-amidehydrochloride

Example 37 (0.1 g) was dissolved in Ethyl Ether (0.8 ml) at roomtemperature, then 1M HCl solution in Ethyl Ether (0.6 ml) was added. Thesuspension was stirred at 3° C. for 3 hour, then filtered and washedwith Ethyl Ether (1 ml) to afford the title compound (0.015 g) as awhite solid.

¹H-NMR (DMSO) δ (ppm) 9.31 (bm, 1H); 9.11 (bm, 1H); 8.02 (bs, 1H); 7.72(bs, 2H); 7.28 (dd, 1H); 7.00 (dd, 1H); 6.84 (m, 1H); 5.34 (q, 1H); 4.54(dd, 1H); 3.50-3.20 (m, 4H); 3.08 (m, 1H); 2.93 (m, 1H); 2.73 (s, 3H);2.38 (s, 3H); 1.48 (d, 3H).

PHARMACY EXAMPLES A. Capsules/Tablets

Active ingredient 20.0 mg  Starch 1500 2.5 mg Microcrystalline 200.0 mg Cellulose Croscarmellose Sodium 6.0 mg Magnesium Stearate 1.5 mg

The active ingredient is blended with the other excipients. The blendcan be used to fill gelatin capsules or compressed to form tablets usingappropriate punches. The tablets can be coated using conventionaltechniques and coatings.

B. Tablets

Active ingredient 20.0 mg Lactose 200.0 mg  Microcrystalline 70.0 mgCellulose Povidone 25.0 mg Croscarmellose  6.0 mg Sodium MagnesiumStearate  1.5 mg

The active ingredient is blended with lactose, microcrystallinecellulose and part of the croscarmellose sodium. The blend is granulatedwith povidone after dispersing in a suitable solvent (i.e. water). Thegranule, after drying and comminution is blended with the remainingexcipients. The blend can be compressed using appropriate punches andthe tablets coated using conventional techniques and coatings.

c) Bolus

Active ingredient 2-60 mg/ml Sodium phosphate 1.0-50.0 mg/ml water forinjection qs to 1 ml

The formulation may be packed in glass ampoules or vials and syringeswith a rubber stopper and a plastic/metal overseal (vials only).

D) Infusion

Active ingredient 2-60 mg/ml Infusion solution (NaCl 0.9% or 5%dextrose) qs to 100 ml

The formulation may be packed in glass vials or plastic bag.

The affinity of the compound of the invention for NK1 receptor wasdetermined using the NK₁-receptor binding affinity method measuring invitro by the compounds' ability to displace [3H]-substance P(SP) fromrecombinant human NK₁ receptors expressed in Chinese Hamster Ovary (CHO)cell membranes. The affinity values are expressed as negative logarithmof the inhibition constant (Ki) of displacer ligands (pKi).

The pKi values obtained as the average of at least two determinationswith representative compounds of the invention are given in thefollowing table:

Example No pki 1 8.97 4 8.36 5 8.67 8 9.37 9 8.81 10 9 12 8.7 14 8.7 169.4 18 9.56 19 9.27 20 9.46 21 8.95 22 9.39 23 9.32 24 9.18 25 9.32 289.31 29 8.87 30 8.78 32 8.59 34 9.10 36 9.81

The ability of the compounds of the invention at the nk1 receptor may bedetermined using the gerbill foot tapping model as described by Rupniak& Williams, Eur. Jour. of Pharmacol., 1994.

The compound was administered orally and one hour later an NK1 agonist(e.g. delta-Aminovaleryl⁶[Pro⁹,Me-Leu¹⁰]-substance P (7-11)) (3 pmol in5 μL icv) was infused directly in the cerebral ventricules of theanimals. The duration of hind foot tapping induced by the NK1 agonist(e.g. delta-Aminovaleryl⁶[Pro⁹,Me-Leu¹⁰]-substance P (7-11)) wasrecorded continuosly for 3 min using a stopclock. The dose of the testcompound required to inhibit by 50% the tapping induced by the NK1agonist (e.g. delta-Aminovaleryl⁶[Pro⁹,Me-Leu¹⁰]-substance P (7-11))expressed as mg/kg was referred as the ID50 values. Alternatively thecompounds may be administered subcutaneously or intraperitoneally.

Representative results obtained for compounds of the invention whengiven by oral administration are given in the following table

Ex No ED_(50 (mg/kg po)) 19 0.04 20 0.065 21 0.4 36 0.05

No untoward effects have been observed when compounds of the inventionhave been administered to the gerbil at the pharmacological activedoses.

1-19. (canceled)
 20. A method for the treatment of a sleep disorderselected from dysomnia, insomnia, and circadian rhythmic disorder, in amammal in need thereof, said method comprising administering aneffective amount of a compound of formula (I):

wherein R is a halogen atom or a C₁₋₄ alkyl group; R₁ is hydrogen or aC₁₋₄ alkyl group; R₂ is hydrogen, a C₁₋₄ alkyl, C₂₋₆ alkenyl or a C₃₋₇cycloalkyl group; or R₁ and R₂ together with nitrogen and carbon atom towhich they are attached respectively are a 5-6 membered heterocyclicgroup; R₃ is a trifluoromethyl, a C₁₋₄ alkyl, a C₁₋₄ alkoxy, atrifluoromethoxy, or a halogen group; R₄ is hydrogen, a (CH₂)_(q)R₇ or a(CH₂)_(r)CO(CH₂)_(p)R₇ group; R₅ is hydrogen, a C₁₋₄ alkyl or a COR₆group; R₆ is hydrogen, hydroxy, amino, methylamino, dimethylamino, a 5membered heteroaryl group containing 1 to 3 heteroatoms selected fromoxygen, sulphur and nitrogen or a 6 membered heteroaryl group containing1 to 3 nitrogen atoms; R₇ is hydrogen, hydroxy or NR₈R₉ wherein R₈ andR₉ are independently hydrogen or C₁₋₄ alkyl optionally substituted byhydroxy, or by amino; R₁₀ is hydrogen, a C₁₋₄ alkyl I group or R₁₀together with R₂ is a C₃₋₇ cycloalkyl group; m is zero or an integerfrom 1 to 3; n is zero or an integer from 1 to 3; both p and r areindependently zero or an integer from 1 to 4; q is an integer from 1 to4; provided that, when R₁ and R₂ together with nitrogen and carbon atomto which they are attached respectively are a 5 to 6 memberedheterocyclic group, i) m is 1 or 2; ii) when m is 1, R is not fluorineand iii) when m is 2, the two substituents R are not both fluorine, or apharmaceutically acceptable salt thereof.
 21. The method of claim 20wherein said mammal is man.
 22. A method for the treatment of insomniain a human in need thereof, said method comprising administering aneffective amount of2-(S)-(4-Fluoro-2-methyl-phenyl)-piperazine-1-carboxylic acid[1-(R)-(3,5-bis-trifluoromethyl-phenyl)-ethyl]-methyl-amidemethanesulphonate.
 23. The method according to claim 22, wherein saidmethod comprises administering orally.
 24. A pharmaceutical tabletcomprising 2-(S)-(4-Fluoro-2-methyl-phenyl)-piperazine-1-carboxylic acid[1-(R)-(3,5-bis-trifluoromethyl-phenyl)-ethyl]-methyl-amidemethanesulphonate.
 25. A method for the treatment of insomnia in a humanin need thereof, said method comprising administering an effectiveamount of 2-(4-fluoro-2-methyl-phenyl)-piperazine-1-carboxylic acid[1-(3,5-bis-trifluoromethyl-phenyl)-ethyl]-methyl-amide or apharmaceutically acceptable salt thereof.
 26. A method for the treatmentof insomnia in a human in need thereof, said method comprisingadministering an effective amount of an enantiomer of2-(4-fluoro-2-methyl-phenyl)-piperazine-1-carboxylic acid[1-(3,5-bis-trifluoromethyl-phenyl)-ethyl]-methyl-amide or apharmaceutically acceptable salt thereof.
 27. A method for the treatmentof insomnia in a human in need thereof, said method comprisingadministering an effective amount of an2-(4-fluoro-2-methyl-phenyl)-piperazine-1-carboxylic acid[1-(3,5-bis-trifluoromethyl-phenyl)-ethyl]-methyl-amide. 28.2-(4-fluoro-2-methyl-phenyl)-piperazine-1-carboxylic acid[1-(3,5-bis-trifluoromethyl-phenyl)-ethyl]-methyl-amide or apharmaceutically acceptable salt thereof.
 29. An enantiomer of2-(4-fluoro-2-methyl-phenyl)-piperazine-1-carboxylic acid[1-(3,5-bis-trifluoromethyl-phenyl)-ethyl]-methyl-amide or apharmaceutically acceptable salt thereof. 30.2-(4-fluoro-2-methyl-phenyl)-piperazine-1-carboxylic acid[1-(3,5-bis-trifluoromethyl-phenyl)-ethyl]-methyl-amide.